New compounds, pharmaceutical compositions and uses thereof

ABSTRACT

The present invention relates to compounds of formula I, 
     
       
         
         
             
             
         
       
     
     wherein R 1 , L P , L Q , X, A, and n are as defined in the application, which have valuable pharmacological properties, and in particular bind to the GPR119 receptor and modulate its activity.

FIELD OF THE INVENTION

The present invention relates to new compounds of formula I

wherein R¹, L^(P), L^(Q), X, A and n are defined as hereinafter, toprocesses for preparing these compounds, to their use as modulators ofthe G-protein-coupled receptor GPR119, to methods for their therapeuticuse, in particular in diseases and conditions mediated by the modulationof the G-protein-coupled receptor GPR119, and to pharmaceuticalcompositions comprising them.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a serious metabolic disease which affects more than100 million people worldwide. In the USA there are more than 12 milliondiabetics with 600,000 new cases diagnosed every year. The prevalence ofdiabetes mellitus is increasing, resulting in a high frequency ofcomplications and a substantial impairment of quality of life and lifeexpectancy. Because of diabetes-associated microvascular complications,in the industrialised countries type 2 diabetes is currently the mostcommon cause of adult-onset loss of vision, renal insufficiency andamputations. In addition, type 2 diabetes is associated with a two- tofive-fold increase in the risk of cardiovascular disease.

The UKPDS study (United Kingdom Prospective Diabetes Study) showed thatintensive treatment with common therapeutic agents, e.g. metformin,sulphonylureas or insulin, results in only a limited improvement inglycaemic control (difference in the HbA1c value ˜0.9%). Moreover,glycaemic control deteriorated considerably over time even in patientsin the intensive treatment group, and this was put down to deteriorationin beta cell function. Diabetes is also a major cause of damage to theretina at the back of the eye and increases the risk of cataract andglaucoma. Finally, diabetes is associated with nerve damage,particularly in the legs and feet, which affects the patient's abilityto feel pain and contributes to serious infections. All in all,complications of diabetes are one of the major causes of deathworldwide.

Adiposity (obesity) is the result of an imbalance between calorie intakeand energy consumption. It correlates to a high degree with insulinresistance and diabetes. However, the molecular mechanisms that areinvolved in obesity/diabetes syndromes are not yet clear. At an earlystage of the development of obesity, an increased insulin secretionbalances out the insulin resistance and protects the patient fromhyperglycaemia. However, after a time, the beta cell function worsensand non-insulin-dependent diabetes develops in about 20% of the obesepopulation. Obesity has thus become a critical risk factor for diabetes,but the factors that predispose one group of patients to a pathologicalchange in insulin secretion as a response to the accumulation of fat arecurrently unknown. Obesity also significantly increases the risk of thedevelopment of cardiovascular disease. Diabetes is also implicated inthe formation of kidney complaints, eye complaints and problems of thenervous system. Kidney disease, also known as nephropathy, sets in whenthe filtering mechanism of the kidneys is disrupted and proteins escapeinto the urine in excessive amounts and finally the kidney fails.Therefore there is a medical need for medicaments for preventing and/ortreating metabolic disorders (particularly diabetes, predominantly type2 diabetes) and the complications thereof. In particular there is a needfor medicaments with good activity in terms of glycaemic control,disease-modifying properties and reducing cardiovascular morbidity andmortality, and which also have a better safety profile.

Dyslipidemia is a disorder of lipoprotein metabolism, includinglipoprotein overproduction or deficiency. Dyslipidemias may bemanifested by elevation of the total cholesterol, LDL cholesterol andtriglyceride and free fatty acid concentrations, and a decrease inhigh-density lipoprotein (HDL) cholesterol concentration in the blood.Dyslipidemia occurs often in situations including diabetes, a commoncause of lipidemia. For adults with diabetes, it has been recommendedthat the levels of LDL, HDL, and total cholesterol, and triglyceride bemeasured every year. Optimal LDL cholesterol levels for adults withdiabetes are less than 100 mg/dL (2.60 mmol/L), optimal HDL cholesterollevels are equal to or greater than 40 mg/dL (1.02 mmol/L), anddesirable triglyceride levels are less than 150 mg/dL (1.7 mmol/L).

GPR119 is a G-protein coupled receptor (also known as GPCR2, RUP3,SNORF25 or GDIR) which is expressed predominantly in the beta cells ofthe pancreas and in the K- and L-cells of the intestine. The GPR119receptor and isoforms have been identified in mammalian speciesincluding human, rat, mouse, hamster, chimpanzee, rhesus monkey, cattleand dog. The expression of GPR119 in the pancreas and particularly inthe pancreatic β-cells led to the hypothesis that the GPR119 receptorcould have effects upon insulin secretion. Activation of the receptorstimulates the cAMP signal pathway, increasing the intracellular levelsof cAMP in these cells. This will lead to an improved diabetic situationby a dual action of such a compound: stimulation of cAMP in the betacell occurs directly via activation of GPR119 in these cells andfurthermore indirectly via stimulation of the release of neuroendocrinepeptides like GIP and GLP-1 and PYY from the gut. The release of thesepeptides may have also additional beneficial effects, e.g. on foodintake, gastric emptying and other yet unknown functions. Also, a GPR119agonist can be expected to bring about an improvement in the beta cellfunction and the beta cell mass. In fact, activation of GPR119stimulates insulin secretion in-vitro and in-vivo (in rodents) in aglucose-dependent manner. The discovery of two endogenous ligands,lysophosphatidylcholine (LPC) and oleoylethanolamide (OEA) as well asmore potent GPR119 agonists have led to the characterization of GPR119as both an insulin and incretin (GLP-1 and GIP) secretagogue receptorcapable of lowering plasma glucose and thereby facilitating glycemiccontrol without the risk of hypoglycemia (Biochem. Biophys. Res. Comm.2005, 744-751; Cell Metabolism 2006, 167-175; Endocrinology 2007,2601-9). It has recently been shown that GPR119 agonists effectivelylower the blood glucose levels in diabetic rodents without the risk ofhypoglycaemia. GPR119 knockout animals have shown that both insulin andincretin secretion induced by GPR119 agonists are dependent upon GPR119receptor. In addition, it has been shown that GPR119 agonists decreasefood intake resulting in weight loss in Sprague Dawley rats. Thereforethe GPR119 agonists may be expected to have a therapeutic benefit inmetabolic diseases. Examples of such diseases include type 1 diabetes,type 2 diabetes, insufficient glucose tolerance, insulin resistance,hyperglycaemia, hyperlipidaemia, hypercholesterolaemia, dyslipidaemia,syndrome X, metabolic syndrome, obesity, high blood pressure, chronicsystemic inflammation, retinopathy, neuropathy, nephropathy,atherosclerosis, endothelial dysfunction and bone-related diseases (suchas osteoporosis, rheumatoid arthritis or osteoarthritis). For comparisonand additional information also see

-   1. Dhayal, S., Morgan, N. G. The significance of GPR119 agonists as    a future treatment for type 2 diabetes. Drug News Perspect. 2010,    23(7), 418-24.-   2. Yoshida, S., Tanaka, H., Oshima, H., Yamazaki, T., Yonetoku, Y.,    Ohishi, T., Matsui, T., Shibasaki, M. AS1907417, a novel GPR119    agonist, as an insulinotropic and β-cell preservative agent for the    treatment of type 2 diabetes. Biochem Biophys Res Commun. 2010,    400(4), 745-51.-   3. Jones, R. M., Leonard, J. N., Buzard, D. J., Lehman, J. GPR119    agonists for the treatment of type 2 diabetes. Expert Opinion on    Therapeutic Patents 2009, Vol. 19, No. 10: 1339-1359.

SUMMARY OF THE INVENTION

The aim of the present invention is to provide new compounds, inparticular new 2,3-dihydro-benzofuran-2-yl-piperidine and2,3-dihydro-furo[2,3-c]pyridin-2-yl-piperidine derivatives, which areactive with regard to the G-protein-coupled receptor GPR119.

Another aim of the present invention is to provide new compounds, inparticular new 2,3-dihydro-benzofuran-2-yl-piperidine and2,3-dihydro-furo[2,3-c]pyridin-2-yl-piperidine derivatives, which areagonists of the G-protein-coupled receptor GPR119.

A further aim of the present invention is to provide new compounds, inparticular new 2,3-dihydro-benzofuran-2-yl-piperidine and2,3-dihydro-furo[2,3-c]pyridin-2-yl-piperidine derivatives, which havean activating effect on the G-protein-coupled receptor GPR119 in vitroand/or in vivo and possess suitable pharmacological and pharmacokineticproperties to use them as medicaments.

A further aim of the present invention is to provide effective GPR119agonists, in particular for the treatment of metabolic disorders, forexample diabetes, dyslipidemia and/or obesity.

A further aim of the present invention is to provide methods fortreating a disease or condition mediated by the activation theG-protein-coupled receptor GPR119 in a patient.

A further aim of the present invention is to provide a pharmaceuticalcomposition comprising at least one compound according to the invention.

A further aim of the present invention is to provide a combination of atleast one compound according to the invention with one or moreadditional therapeutic agents.

A further aim of the present invention is to provide methods for thesynthesis of the new compounds, in particular2,3-dihydro-benzofuran-2-yl-piperidine and2,3-dihydro-furo[2,3-c]pyridin-2-yl-piperidine derivatives.

A further aim of the present invention is to provide starting and/orintermediate compounds suitable in methods for the synthesis of the newcompounds.

Further aims of the present invention become apparent to the one skilledin the art by the description hereinbefore and in the following and bythe examples.

It has now been found that the compounds according to the inventiondescribed in more detail hereinafter have surprising and particularlyadvantageous properties, and in particular as GPR119 agonists.

In a first aspect the invention thus relates to a compound of formula I

wherein

-   R¹ is selected from the group R¹-G1 consisting of    C₃₋₆-cycloalkyl-CH₂— and linear or branched C₁₋₅-alkyl-, wherein the    C₃₋₆-cycloalkyl and the C₁₋₅-alkyl group are optionally substituted    with one or more F atoms and/or one CF₃ group, and wherein the alkyl    group may be substituted from position 2 onwards; and-   A is selected from the group A-G1 consisting of a    1,2,3,6-tetrahydropyridin-4-yl group substituted at the N with    C₁₋₄-alkyl-S(═O)₂—, a piperidin-4-yl group substituted at the N with    C₁₋₄-alkyl-S(═O)₂—, and a phenyl group substituted with a group T    and optionally additionally substituted with one or two groups    independently selected from F and CH₃; and-   T is selected from the group T-G1 consisting of F, Cl, Br, I, CN,    OH, NO₂, C₁₋₆-alkyl-, C₁₋₆-alkenyl-, C₁₋₆-alkynyl-, C₃₋₆-cycloalkyl,    C₁₋₆-alkyl-O—, C₃₋₆-cycloalkyl-O—, C₁₋₆-alkyl-S—, HO—C(═O)—,    C₁₋₆-alkyl-O—C(═O)—, C₁₋₄-alkyl-C(═O)—, C₃₋₆-cycloalkyl-C(═O)—,    C₁₋₄-alkyl-S(═O)—, C₁₋₄-alkyl-S(═O)₂—, R^(NT1)R^(NT2)N—,    R^(NT1)R^(NT2)N—C(═O)—, R^(NT1)R^(NT2)N—S(═O)₂—,    R^(NT1)R^(NT2)N—C(═O)—(R^(N))N—, heterocyclyl, heterocyclyl-O—,    aryl, aryl-O—, heteroaryl and heteroaryl-O—, wherein each alkyl,    alkenyl, alkynyl, and cycloalkyl group may be optionally substituted    with one or more substituents independently of each other selected    from F, Cl, CN, OH, C₁₋₃-alkyl, C₃₋₆-cycloalkyl, C₁₋₃-alkyl-O—,    R^(NT1)R^(NT2)N—, R^(NT1)R^(NT2)N—C(═O)—, C₁₋₄-alkyl-S(═O)—,    C₁₋₄-alkyl-S(═O)₂—, R^(NT1)R^(NT2)N—S(═O)₂— aryl, heteroaryl, and    heterocyclyl, and    -   wherein aryl denotes phenyl or naphthyl, and    -   wherein heteroaryl is a 5- or 6-membered aromatic ring which        contains 1, 2, 3 or 4 heteroatoms independently of each other        selected from N, O and S, wherein the H-atom in one or more NH        groups may be optionally replaced by R^(N); and    -   wherein heterocyclyl is a 4- to 7-membered unsaturated or        saturated carbocyclic ring in which 1 or 2 —CH₂-groups        independently of each other are replaced by NR^(N), O, —C(═O)—,        S, —S(═O)— or —S(═O)₂—, and/or in which a —CH— group is replaced        by N; and    -   wherein each aryl, heteroaryl or heterocyclyl group may be        optionally substituted with one or more substituents        independently of each other selected from L^(A); and-   R^(N) independently of each other is selected from the group    R^(N)-G1 consisting of H, C₁₋₄-alkyl, C₁₋₄-alkyl-C(═O)—, and    C₁₋₄-alkyl-S(═O)₂—; and-   R^(NT1) is selected from the group R^(NT1)-G1 consisting of H,    C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-alkyl-C(═O)—, C₁₋₆-alkyl-S(═O)₂,    heterocyclyl, aryl and heteroaryl,    -   wherein each alkyl and cylcoalkyl group may be optionally        substituted with one or more substituents independently of each        other selected from the group consisting of F, OH, CN,        C₁₋₄-alkyl, C₁₋₄-alkyl-O—, R^(N) ₂N, C₁₋₄-alkyl-S(═O)₂—,        C₃₋₆-cycloalkyl, heterocyclyl, phenyl and heteroaryl; and    -   wherein heterocyclyl may be optionally substituted with one or        more substituents independently of each other selected from F,        C₁₋₄-alkyl, R^(N) ₂N, OH and C₁₋₄-alkyl-O—; and    -   wherein heterocyclyl is a C₄₋₇-cycloalkyl ring in which 1 or 2        —CH₂-groups independently of each other are replaced by NR^(N),        O, C(═O), S, S(═O) or S(═O)₂; and    -   wherein aryl is phenyl or naphthyl; and    -   wherein heteroaryl is a 5- or 6-membered aromatic ring which        contains 1, 2 or 3 heteroatoms independently of each other        selected from N, O and S, wherein the H-atom in one or more NH        groups may be optionally replaced by R^(N); and    -   wherein aryl and heteroaryl may be optionally substituted with        one or more substituents L^(A); and-   R^(NT2) is selected from the group R^(NT2)-G1 consisting of H and    C₁₋₆-alkyl; or-   R^(NT1) and R^(NT2) are linked to form one group selected from the    group R^(NT1)R^(NT2)-G1 consisting of a C₃₋₅-alkylene group, wherein    1 or 2 —CH₂-groups independently of each other are replaced by    NR^(N), O, C(═O), S, S(═O) or S(═O)₂; and which may be optionally    substituted with one or more substituents independently of each    other selected from F, C₁₋₄-alkyl, (R^(N))₂N, OH and C₁₋₄-alkyl-O—;-   L^(A) is selected from the group L^(A)-G1 consisting of F, Cl, Br,    CN, OH, NO₂, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, (R^(N))₂N—C(═O),    (R^(N))₂N—, and C₁₋₄-alkyl-S(═O)₂—, wherein each alkyl group may be    optionally substituted with one or more substituents independently    of each other selected from F, Cl, CN, OH and C₁₋₃-alkyl-O—; and-   L^(P) is selected from the group L^(P)-G1 consisting of F and    C₁₋₃-alkyl, wherein the alkyl group may be substituted with one or    more F-atoms; and-   L^(Q) is selected from the group L^(Q)-G1 consisting of H and    C₁₋₃-alkyl; and-   X is selected from the group X-G1 consisting of CH and N; and-   n is an integer selected from 0, 1, 2, 3 and 4;    including any tautomers and stereoisomers thereof,    or a salt thereof,    or a solvate or hydrate thereof.

In a further aspect the present invention relates to processes forpreparing a compound of general formula I and to new intermediatecompounds in these processes.

A further aspect of the invention relates to a salt of the compounds ofgeneral formula I according to this invention, in particular to apharmaceutically acceptable salt thereof.

In a further aspect this invention relates to a pharmaceuticalcomposition, comprising one or more compounds of general formula I orone or more pharmaceutically acceptable salts thereof according to theinvention, optionally together with one or more inert carriers and/ordiluents.

In a further aspect this invention relates to a method for treatingdiseases or conditions which are mediated by activating theG-protein-coupled receptor GPR119 in a patient in need thereofcharacterized in that a compound of general formula I or apharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided a methodfor treating a metabolic disease or disorder in a patient in needthereof characterized in that a compound of general formula I or apharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided the useof a compound of the general formula I or a pharmaceutically acceptablesalt thereof for the manufacture of a medicament for a therapeuticmethod as described hereinbefore and hereinafter.

According to another aspect of the invention, there is provided acompound of the general formula I or a pharmaceutically acceptable saltthereof for use in a therapeutic method as described hereinbefore andhereinafter.

In a further aspect this invention relates to a method for treating adisease or condition mediated by the activation of the G-protein-coupledreceptor GPR119 in a patient that includes the step of administering tothe patient in need of such treatment a therapeutically effective amountof a compound of the general formula I or a pharmaceutically acceptablesalt thereof in combination with a therapeutically effective amount ofone or more additional therapeutic agents.

In a further aspect this invention relates to a use of a compound of thegeneral formula I or a pharmaceutically acceptable salt thereof incombination with one or more additional therapeutic agents for thetreatment of diseases or conditions which are mediated by the activationof the G-protein-coupled receptor GPR119.

In a further aspect this invention relates to a pharmaceuticalcomposition which comprises a compound according to general formula I ora pharmaceutically acceptable salt thereof and one or more additionaltherapeutic agents, optionally together with one or more inert carriersand/or diluents.

Other aspects of the invention become apparent to the one skilled in theart from the specification and the experimental part as describedhereinbefore and hereinafter.

DETAILED DESCRIPTION

Unless otherwise stated, the groups, residues, and substituents,particularly A, R¹, T, R^(N), R^(NT1), R^(NT2), L^(A), L^(P), L^(Q), X,and n are defined as above and hereinafter. If residues, substituents,or groups occur several times in a compound, as for example R^(N) orL^(P), they may have the same or different meanings. Some preferredmeanings of individual groups and substituents of the compoundsaccording to the invention will be given hereinafter. Any and each ofthese definitions may be combined with each other.

R¹: R¹-G1:

The group R¹ is preferably selected from the group R¹-G1 as definedhereinbefore and hereinafter.

R¹-G1a:

According to one embodiment the group R¹ is selected from the groupR¹-G1a consisting of C₃₋₆-cycloalkyl-CH₂— and C₁₋₃-alkyl-CH₂—, whereinthe C₃₋₆-cycloalkyl and the C₁₋₃-alkyl group are optionally substitutedwith one to three F atoms and/or one CF₃ group.

R¹-G2:

According to another embodiment the group R¹ is selected from the groupR¹-G2 consisting of 2-fluoro-2-methyl-propyl and(1-trifluoromethyl-cyclopropyl)-methyl.

R¹-G3:

According to one embodiment the group R¹ is selected from the groupR¹-G3 consisting of 2-fluoro-2-methyl-propyl.

R¹-G4:

According to one embodiment the group R¹ is selected from the groupR¹-G4 consisting of (1-trifluoromethyl-cyclopropyl)-methyl.

R^(N) R^(N)-G1:

The group R^(N) is preferably selected from the group R^(N)-G1 asdefined hereinbefore and hereinafter.

R^(N)-G2:

In another embodiment the group R^(N) is selected from the groupR^(N)-G2 consisting of H, C₁₋₃-alkyl, C₁₋₃-alkyl-carbonyl, andC₁₋₃-alkyl-sulfonyl.

R^(N)-G3:

In another embodiment the group R^(N) is selected from the groupR^(N)-G3 consisting of H, methyl, methylcarbonyl, and methylsulfonyl.

A: A-G1:

The group A is preferably selected from the group A-G1 as definedhereinbefore and hereinafter.

A-G2:

In another embodiment the group A is selected from the group A-G2consisting of:

wherein the phenyl group is optionally additionally substituted with oneor two groups independently selected from F and CH₃, and T is as definedhereinbefore and hereinafter.

A-G3:

In another embodiment the group A is selected from the group A-G3consisting of:

wherein the phenyl groups are optionally substituted with one or twogroups independently selected from F and CH₃.

A-G3a:

In another embodiment the group A is selected from the group A-G3aconsisting of:

wherein the phenyl groups are optionally substituted with one F-atom.

A-G4:

In another embodiment the group A is selected from the group A-G4consisting of:

A-G5:

In another embodiment the group A is selected from the group A-G5consisting of:

T T-G1:

The group T is preferably selected from the group T-G1 as definedhereinbefore and hereinafter.

T-G2:

According to one embodiment the group T is selected from the group T-G2consisting of CN, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-alkyl-O—C(═O)—,C₁₋₄-alkyl-C(═O)—, C₁₋₄-alkyl-S(═O)—, C₁₋₄-alkyl-S(═O)₂—,C₁₋₄-alkyl-S(═O)₂—C₁₋₄-alkyl-, R^(NT1)R^(NT2)N—C(═O)—,R^(NT1)R^(NT2)N—S(═O)₂—, C₁₋₄-alkyl-S(═O)₂—(R^(N))N—, R^(NT1)R^(NT2)N,R^(NT1)R^(NT2)N—C(═O)—C₁₋₄-alkyl-, wherein each alkyl group may beoptionally substituted with one or more substituents independently ofeach other selected from F, Cl, CN, OCH₃, and OH.

T-G3:

According to another embodiment the group T is selected from the groupT-G3 consisting of CN, C₁₋₄-alkyl-S(═O)₂—CH₂—, C₁₋₄-alkyl-S(═O)₂—,R^(NT1)R^(NT2)N—S(═O)₂—, R^(NT1)R^(NT2)N—C(═O)—,C₁₋₄-alkyl-S(═O)₂—(R^(N))N—, and R^(NT1)N^(RT2)N—.

T-G4:

According to another embodiment the group T is selected from the groupT-G4 consisting of C₁₋₄-alkyl-S(═O)₂—CH₂— and C₁₋₄-alkyl-S(═O)₂—.

R^(NT1) R^(NT1)-G1:

R^(NT1) is preferably selected from the group R^(NT1)-G1 as definedhereinbefore and hereinafter.

R^(NT1)-G2:

In another embodiment R^(NT1) is selected from the group R^(NT1)-G2consisting of H, C₁₋₄-alkyl and C₃₋₆-cycloalkyl, wherein each alkyl andcylcoalkyl group may be optionally substituted with one or twosubstituents independently of each other selected from the groupconsisting of F, CH₃, OH and C₁₋₃-alkyl-O—.

R^(NT1)-G3:

In another embodiment R^(NT1) is selected from the group R^(NT1)-G3consisting of H and C₁₋₄-alkyl.

R^(NT2) R^(NT2)-G1:

R^(NT2) is preferably selected from the group R^(NT2)-G1 as definedhereinbefore and hereinafter.

R^(NT2)-G2:

In another embodiment R^(NT2) is selected from the group R^(NT2)-G2consisting of H and C₁₋₃-alkyl.

R^(NT2)-G3:

In another embodiment R^(NT2) is selected from the group R^(NT2)-G3consisting of H and methyl.

R^(NT2)-G4:

In another embodiment R^(NT2) is selected from the group R^(NT2)-G4consisting of H.

R^(NT1)R^(NT2) R^(NT1)R^(NT2)-G1:

According to one embodiment the groups R^(NT1) and R^(NT2) are linkedand form a group which is selected from the group R^(NT1)R^(NT2)-G1 asdefined hereinbefore and hereinafter.

R^(NT1)R^(NT2)-G2:

According to another embodiment the groups R^(NT1) and R^(NT2) arelinked and together with the N-atom to which they are attached form agroup which is selected from the group R^(NT1)R^(NT2)-G2 consisting ofazetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,piperazin-2-onyl, N—C₁₋₃-alkyl-piperazinyl,N—C₁₋₃-alkyl-piperazin-2-onyl, and N—(C₁₋₃-alkyl-C(═O))-piperazinyl,which may be optionally substituted with one or more substituentsindependently of each other selected from the group consisting of F, HO,C₁₋₃-alkyl, C₁₋₃-alkyl-O—, and (R^(N))₂N.

R^(NT1)R^(NT2)-G3:

According to another embodiment the groups R^(NT1) and R^(NT2) arelinked and together with the N-atom to which they are attached form agroup which is selected from the group R^(NT1)R^(NT2)-G3 consisting ofazetidinyl, pyrrolidinyl, piperidinyl and morpholinyl, which may each beoptionally substituted with one or two substituents independently ofeach other selected from the group consisting of F, OH, CH₃ and CH₃—O—.

L^(A): L^(A)-G1:

The group L^(A) is preferably selected from the group L^(A)-G1 asdefined hereinbefore and hereinafter.

L^(A)-G2:

In another embodiment the group L^(A) is selected from the groupL^(A)-G2 consisting of F, Cl, Br, CN, OH, C₁₋₃-alkyl-, C₁₋₃-alkyl-O—,H₂N—, C₁₋₃-alkyl-NH— and (C₁₋₃-alkyl)₂N—, wherein the C₁₋₃-alkyl- andC₁₋₃-alkyl-O— group may be optionally substituted with one or moreF-atoms.

L^(A)-G3:

In another embodiment the group L^(A) is selected from the groupL^(A)-G3 consisting of F, Cl, CH₃—, and CF₃.

X X-G1:

The group X is preferably selected from the group X-G1 as definedhereinbefore and hereinafter.

X-G2:

In another embodiment the group X is selected from the group X-G2consisting of CH.

X-G3:

In another embodiment the group X is selected from the group X-G3consisting of N.

L^(P): L^(P)-G1:

The group L^(P) is preferably selected from the group L^(P)-G1 asdefined hereinbefore and hereinafter.

L^(P)-G2:

In another embodiment the group L^(P) is selected from the groupL^(P)-G2 consisting of F and methyl.

L^(Q): L^(Q)-G1:

The group L^(Q) is preferably selected from the group L^(Q)-G1 asdefined hereinbefore and hereinafter.

L^(Q)-G2:

In another embodiment the group L^(Q) is selected from the groupL^(Q)-G2 consisting of H and methyl.

L^(Q)-G3:

In another embodiment the group L^(Q) is selected from the groupL^(Q)-G2 consisting of methyl.

L^(Q)-G4:

In another embodiment the group L^(Q) is selected from the groupL^(Q)-G2 consisting of H.

n:

The index n is an integer selected from 0, 1, 2, 3 or 4.

According to one embodiment the index n is 0, 1 or 2, in particular 0 or1.

According to another embodiment the index n is 0.

The following preferred embodiments of compounds of the formula I aredescribed using generic formulas (I.1) and (I.2), wherein any tautomersand stereoisomers, solvates, hydrates and salts thereof, in particularthe pharmaceutically acceptable salts thereof, are encompassed.

wherein in each of the above formulas (I.1) and (I.2), the groups R¹,L^(Q), and A are defined as hereinbefore and hereinafter.

Further preferred embodiments of compounds of the formula I aredescribed by generic formulas (I.R) and (I.S), wherein any tautomers andstereoisomers, solvates, hydrates and salts thereof, in particular thepharmaceutically acceptable salts thereof, are encompassed.

wherein in each of the above formulas (I.R) and (I.S), the groups R¹,L^(Q), X, and A are defined as hereinbefore and hereinafter.

Examples of preferred subgeneric embodiments according to the presentinvention are set forth in the following table, wherein each substituentgroup of each embodiment is defined according to the definitions setforth hereinbefore and wherein all other substituents of the formula Iare defined according to the definitions set forth hereinbefore:

Embodiment Formula R¹- A- L^(Q)- X- E-1 I R¹-G1 A-G1 L^(Q)-G2 X-G1 E-2 IR¹-G2 A-G2 L^(Q)-G2 X-G1 E-3 I R¹-G2 A-G3 L^(Q)-G2 X-G1 E-4 I R¹-G2 A-G4L^(Q)-G2 X-G1 E-5 I R¹-G2 A-G5 L^(Q)-G2 X-G1 E-6 I.1 R¹-G1 A-G1 L^(Q)-G4— E-7 I.1 R¹-G2 A-G2 L^(Q)-G4 — E-8 I.1 R¹-G2 A-G3 L^(Q)-G4 — E-9 I.1R¹-G2 A-G4 L^(Q)-G4 — E-10 I.1 R¹-G2 A-G5 L^(Q)-G4 — E-11 I.2 R¹-G1 A-G1L^(Q)-G2 — E-12 I.2 R¹-G2 A-G2 L^(Q)-G2 — E-13 I.2 R¹-G2 A-G3 L^(Q)-G2 —E-14 I.2 R¹-G2 A-G4 L^(Q)-G2 — E-15 I.2 R¹-G2 A-G5 L^(Q)-G2 — E-16 I.RR¹-G1 A-G1 L^(Q)-G2 X-G1 E-17 I.R R¹-G2 A-G2 L^(Q)-G2 X-G1 E-18 I.RR¹-G2 A-G3 L^(Q)-G2 X-G1 E-19 I.R R¹-G2 A-G4 L^(Q)-G2 X-G1 E-20 I.RR¹-G2 A-G5 L^(Q)-G2 X-G1 E-21 I.S R¹-G1 A-G1 L^(Q)-G2 X-G1 E-22 I.SR¹-G2 A-G2 L^(Q)-G2 X-G1 E-23 I.S R¹-G2 A-G3 L^(Q)-G2 X-G1 E-24 I.SR¹-G2 A-G4 L^(Q)-G2 X-G1 E-25 I.S R¹-G2 A-G5 L^(Q)-G2 X-G1

Preferred are those compounds of formula I, wherein

-   X is N;-   R¹ is

-   A is

wherein the phenyl group is optionally additionally substituted with oneor two groups independently selected from F and CH₃;

-   T is C₁₋₄-alkyl-S(═O)₂—CH₂— or C₁₋₄-alkyl-S(═O)₂—;-   L^(Q) is H or CH₃;-   n is 0;    and the pharmaceutically acceptable salts thereof.

More preferred are those compounds of formula I, wherein

-   X is N;-   R¹ is

-   A is

-   L^(Q) is H or CH₃;-   n is 0;    and the pharmaceutically acceptable salts thereof.

Particularly preferred compounds, including their tautomers andstereoisomers, the salts thereof, or any solvates or hydrates thereof,are described in the experimental section hereinafter.

The following compounds are mentioned as examples of compounds accordingto the invention:

including any tautomers and stereoisomers thereof, or a salt thereof ora solvate or hydrate thereof.

The compounds according to the invention and their intermediates may beobtained using methods of synthesis which are known to the one skilledin the art and described in the literature of organic synthesis.Preferably the compounds are obtained analogously to the methods ofpreparation explained more fully hereinafter, in particular as describedin the experimental section. In some cases the sequence adopted incarrying out the reaction schemes may be varied. Variants of thesereactions that are known to the skilled man but are not described indetail here may also be used. The general processes for preparing thecompounds according to the invention will become apparent to the skilledman on studying the schemes that follow. Starting compounds arecommercially available or may be prepared by methods that are describedin the literature or herein, or may be prepared in an analogous orsimilar manner. Before the reaction is carried out any correspondingfunctional groups in the compounds may be protected using conventionalprotecting groups. These protecting groups may be cleaved again at asuitable stage within the reaction sequence using methods familiar tothe skilled man.

Compounds of the invention I are accessible using the synthetic routesketched in Scheme 1; R¹, L^(P), n, X, and A have the meanings asdefined hereinbefore and hereinafter. Starting with compound 1 thetarget compounds are obtained upon partial reduction of the benzofuran.The reaction is preferably conducted with hydrogen as the reducing agentin the presence of a transition metal catalyst. Suited transition metalsmay be derived from Ni, Pd, Pt, Ir, and Rh, such as Raney nickel, Pd oncarbon, Pt on carbon, Rh on carbon, PtO₂, and Rh₂O₃. The reduction ispreferably carried out in tetrahydrofuran, acetone, ethyl acetate,alcohol, e.g. methanol, ethanol, or isopropanol, acetic acid, ormixtures thereof, at hydrogen pressures of 1 to 100 bar, at 0 to 120° C.Alternatively, formic acid or a formate salt instead of hydrogen may beused as reducing agent.

The reduction may also be accomplished with a silane or sodium amalgamas reducing agent. Reduction using a silane is for example conductedwith triethylsilane and trifluoroacetic acid in dichloromethane,chloroform, acetonitrile, mixtures thereof, or without a solvent intrifluoroacetic acid, at −20 to 120° C. Sodium amalgam is frequentlyemployed in an aqueous solution with sodium hydroxide or sodiumbicarbonate.

Compound 1, in turn, may be obtained from compound 4, bearing tworeplaceable halogen or pseudo-halogen groups, as described in Scheme 2;R¹, L^(P), n, X, and A have the meanings as defined hereinbefore andhereinafter. Depending on the reactivity of the two carbon atoms bearingthe halogen or pseudo-halogen groups, the two coupling partners, 6 and5, are introduced following the sequence depicted on the top or bottomof the scheme. Both residues are preferably attached via a transitionmetal catalyzed reaction, preferably mediated by a palladium, nickel,copper, or iron species. The active catalyst may be derived from anelemental form of the transition metal, such as palladium on carbon ornanoparticles of iron or palladium, or a salt of the transition metal,such as fluoride, chloride, bromide, acetate, triflate, ortrifluoroacetate, which are preferably combined with ligands, such asphosphines, e.g. tri-tert-butylphosphine, tricyclohexylphosphine,optionally substituted biphenyl-dicyclohexyl-phosphines, optionallysubstituted biphenyl-di-tert-butyl-phosphines,1,1′-bis(diphenylphosphino)-ferrocene, triphenylphosphine,tritolylphosphine, or trifurylphosphine, phosphites, 1,3-disubstitutedimidazole carbenes, 1,3-disubstituted imidazolidine carbenes,dibenzylideneacetone, allyl, or nitriles. A-M is preferably a boronicacid, trifluoroborate, boronic ester, zinc halide, or magnesium halideof A and alkyne 5 is preferably used as is or zinc acetylide. Dependingon the nucleophiles the reactions are preferably conducted in benzene,toluene, ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone,alcohol, water, or mixtures thereof, at −10 to 160° C. Additives such ashalide salts, e.g. lithium chloride, potassium fluoride,tetrabutylammonium fluoride, hydroxide sources, such as potassiumhydroxide, potassium carbonate, amines, such as triethylamine,diisopropylamine, and ethyldiisopropylamine, silver salts, such assilver oxide or triflate, and/or copper salts, such as copper iodide orchloride or copper thiophene-2-carboxylate, may be beneficial or evenessential for the reaction to proceed. The conditions for the couplingof alkyne 5 with one of the electrophiles, 2 or 4, may bring about thesubsequent cyclization as well and thus provide the benzofuran. Forinstance, with Pd(PPh₃)₂Cl₂, CuI, and triethylamine inN,N-dimethylformamide at 20 to 140° C. the benzofuran may be obtaineddirectly. If the intermediate alkyne is obtained the benzofuran may beformed in a separate step using, for example, Bu₄NF in tetrahydrofuranat 50 to 70° C., NaOH in aqueous solution at elevated temperature, CuIor CuCN, optionally in the presence of NEt₃, in N,N-dimethylformamide atelevated temperature, AuCl(PPh₃) and AgOSO₂CF₃ in CH₂Cl₂ ortetrahydrofuran, AgOSO₂CF₃, optionally in the presence oftrifluoroacetic acid, in CH₂Cl₂, Pd, e.g. PdCl₂, or other transitionmetals such as Rh. The benzofuran may also be assembled from aconstellation in which the oxygen to cyclize (oxygen at the carbon atomnext to the carbon atom bearing the alkynyl group) is embedded in anamide group of an aza-heterocyclic group provided that the additionalgroup on the amide N is cleavable under the reaction conditions (seee.g. Synthesis 2007, 3117). The reactivities of the reaction partners(reacting carbons) described may be reversed, i.e. compounds 2, 3, and 4are the nucleophile bearing M and compounds and 6 are the electrophilebearing Hal¹ or Hal², providing the same products under the same orsimilar conditions.

Another viable route to synthesize compounds of the invention employsbenzofuran derivative 7 as origin (Scheme 3); R¹, L^(P), n, X, and Ahave the meanings as defined hereinbefore and hereinafter. Compound 7and piperidine 11 are preferably combined by a transition metalcatalyzed process as described above for Scheme 2. The reactivity of the2-position of the benzofuran 7 determines the suited piperidine 11 forthe coupling reaction. Benzofurans bearing Cl, Br, or I at the2-position are preferably matched with, e.g., tetrahydropyridinesbearing for Z B(OH)₂, B(OCMe₂CMe₂O), or BF₃K. Reversing the reactivityof 7, i.e. 7 is the nucleophilic partner bearing M, e.g. B(OH)₂ orB(OCMe₂CMe₂O), demands a piperidine of opposite reactivity, i.e.tetrahydropyridines bearing for Z, e.g., OSO₂CF₃ or Cl. Moreover,piperidin-4-ones (Z=═O) may be coupled with electrophilic benzofurans 7(Y=Cl, Br, I) using tosylhydrazone, a base such as LiOtBu, and a Pdcatalyst in a solvent such as 1,4-dioxane (see e.g. Chem. Eur. J. 2008,14, 4792-5, and Org. Lett. 2010, 12, 4042-5, and references quotedtherein). The additional double-bond in the product due to the use of atetrahydropyridine may be reduced along with the benzofuran in the nextreaction step as described above for Scheme 1. Halogenation with Cl, Br,or I of compound 9 delivers compound 10. Chlorination is accomplishedwith, for example, N-chlorosuccinimide, chlorine, or sulfuryl chloride.N-chlorosuccinimide is preferably used in the presence of a Lewis acid,e.g. ZrCl₄ or HCl, in dichloromethane, acetonitrile,N,N-dimethylformamide, methanol, water, or acetic acid; chlorine ispreferably employed in chloroform or acetic acid, and sulfuryl chloridein dichloromethane and chloroform. Bromination is preferably achievedusing bromine or N-bromosuccinimide in dichloromethane, acetonitrile, oracetic acid, optionally in the presence of a Lewis acid. Iodine may beintroduced with, e.g., iodine combined with silver nitrate, iodine insulfuric acid, N-iodosuccinimide combined with indium triflate, oriodine chloride in acetic acid or dichloromethane. The concluding stepin Scheme 3, transition metal catalyzed coupling of 10 and 6, may becarried out in analogy to the proceeding described above.

Scheme 4 shows another way of synthesis of compounds of the invention;R¹, L^(P), L^(Q), n, X, and A have the meanings as defined hereinbeforeand hereinafter. The sequence commences with addition of hydride or analkyl group to ketone 12 to obtain alcohol 13. Hydride addition ispreferably conducted with a complex metal hydride, such as sodiumborohydride, lithium borohydride, lithium triethylborohydride,diisobutylaluminum hydride, or lithium aluminum hydride. Sodiumborohydride is usually used in aqueous or alcoholic solutions at −20 to100° C., while the other reagents are preferably employed indichloromethane, 1,2-dichloroethane, hexanes, ether, 1,4-dioxane,tetrahydrofuran, N-methylpyrrolidone, benzene, toluene, or mixturesthereof, at −80 to 60° C. The reduction may also be conducted in astereoselective fashion to access only one enantiomer using, e.g., theconditions of the Corey-Bakshi-Shibata (CBS) reduction (also calledCorey-Itsuno reduction). Addition of an alkyl group may be accomplishedby adding an alkyl lithium or magnesium halide to ketone 12. Thereaction is preferably conducted in tetrahydrofuran, ether, toluene,hexanes, or mixtures thereof at −78 to 0° C. The addition of lanthanidesalts, e.g. CeCl₃, can be beneficial to the reaction. Intramolecularsubstitution of the leaving group LG with oxygen provides targetcompound I″. For LG equals F, SO₂C₁₋₄-alkyl, SO₂-aryl, or NO₂, thereaction is preferably carried out in the presence of a base, such asNaH, CaH₂, BuLi, KO^(t)Bu, or KOH, in toluene, tetrahydrofuran,1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, or mixtures thereof, at 20 to 200° C. For LG is Cl,Br, or I, the reaction is preferably conducted in the presence of atransition metal catalyst, such as a Pd or Cu species.

The dihydrofuran ring may also be formed from compound 13′, bearing anadditional hydroxy group on the aromatic ring. Intramolecularsubstitution of the aliphatic OH group with the aromatic 0 group may beaccomplished using a phosphine and an azodicarboxylic ester or amide intetrahydrofuran, 1,4-dioxane, diethyl ether, toluene, benzene,dichloromethane, or mixtures thereof, at −30 to 100° C. (Mitsunobureaction). Common combinations for this transformation aretriphenylphosphine or tributylphosphine and dimethyl azodicarboxylate,diethyl azodicarboxylate, diisopropyl azodicarboxylate,di-(4-chlorobenzyl) azodicarboxylate, dibenzyl azodicarboxylate,di-tert-butyl azodicarboxylate, azodicarboxylic acidbis-(dimethylamide), azodicarboxylic acid dipiperidide, orazodicarboxylic acid dimorpholide. Alternatively, the aliphatic OH groupmay be transformed into a leaving group, such as Cl, Br, I, OSO₂CH₃, andOSO₂Ph, and then displaced with the aromatic O under basic conditions.Suited bases may be, for instance, carbonates, e.g. Cs₂CO₃ and K₂CO₃,hydrides, e.g. NaH, alcoholates, e.g. NaOMe and KO^(t)Bu, hydroxides,e.g. KOH and NaOH, that are preferably employed in toluene,tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidinone, dimethyl sulfoxide, alcohol, water, and mixturesthereof. The reaction may be carried out such that the aliphatic hydroxygroup is substituted with complete inversion of configuration deliveringan enantiomerically enriched or pure product provided that anenantiomerically enriched or pure starting compound is used.

Intermediate 12 may be accessed as delineated in Scheme 6; R¹, L^(P), n,X, and A have the meanings as defined hereinbefore and hereinafter. Acarboxylic acid derivative 14 can be merged with an aromatic compound15, that bears an anionic carbon center attached to the aromatic ring,to provide intermediate 12′ (route a.). Suited carboxylic acidderivatives may be e.g. carboxylic halides, carboxylic esters,carboxylic anhydrides, and carboxylic amides, while suited nucleophileprecursors 15 are preferably derived from an electron deficient aromaticor heteroaromatic, e.g., pyridine, or bear an electron-withdrawing group(EWG) at the carbon center to generate the negative charge more easily;preferred EWG are carboxylic esters and cyano. The reaction is mediatedby a base that deprotonates compound 15 to generate the anion which, inturn, adds to the carboxylic function of 14 to give 12′; the aniongenerating step may be carried out in the presence or prior to theaddition of compound 14. Most preferred bases are selected fromalcoholates, e.g. KO^(t)Bu and NaOMe, amines, e.g. triethylamine and1,8-diazabicyclo[5.4.0]undec-7-ene, carbonates, e.g. Cs₂CO₃ and K₂CO₃,hydroxides, e.g. NaOH and KOH, and amides, e.g. LiN(SiMe₃)₂ andLiN^(i)Pr₂, that, depending on their reactivity and compatibility, maybe used in solvents such as toluene, tetrahydrofuran, 1,4-dioxane,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone,dimethyl sulfoxide, alcohol, or mixtures thereof. For example, acompound 14 bearing an ester function (Y=O—C₁₋₄-alkyl) may be combinedwith a compound 15 bearing a cyano or ester group (EWG=CN orC(═O)OC₁₋₄-alkyl) using KO^(t)Bu or NaOEt as base and tetrahydrofuran,N-methylpyrrolidinone, or ethanol as solvent. The product 12′ may betransformed into intermediate 12 by hydrolysis of the ester or cyanogroup followed by decarboxylation of the resulting carboxylic acidfunction. EWG groups such as nitro or sulfonyl can be removed as well.

Combination of compounds 16 and 17 is another way of synthesis forintermediate 12 (route b.). Depending on the reactivity of the couplingpartners, the reaction is best conducted in the presence of a transitionmetal catalyst or without an additive. For example, compound 16 bearinga boronic acid (M=B(OH)₂) and compound 17 having a carboxylic chloride(Z=Cl) may be coupled using a Pd catalyst, e.g. Pd(PPh₃)₄, and a base,e.g. K₃PO₄, in a solvent, e.g. toluene or 1,4-dioxane, at 60 to 120° C.A compound 16 with M=Li or MgCl may be matched with an electrophile 17bearing a carboxamide group (Z=N(OMe)Me). The reaction is commonlyconducted in tetrahydrofuran, 1,4-dioxane, ether, toluene, or mixturesthereof, at −70 to 40° C., optionally in the presence of an additivesuch as CeCl₃. Compound 12″ may be converted to intermediate 12 byreduction of the double bond with hydrogen or a formate salt in thepresence of a transition metal, e.g. Pd on carbon, or a hydride, e.g.[CuH(PPh₃)]₆.

A general way of attaching residue R¹ to the N atom of the piperidine ofthe compounds of the invention or an intermediate towards them issketched in Scheme 7; R¹, L^(P), and n have the meanings as definedhereinbefore and hereinafter. The residue R¹ may be attached to thepiperidine N using an electrophilic R¹ group, bearing a leaving group atthe CH₂ unit to be attached such as Cl, Br, I, OSO₂C₁₋₄-alkyl, OSO₂aryl,or OSO₂CF₃, in the presence of a base, e.g. Na₂CO₃, K₂CO₃, or Cs₂CO₃,pyridine, 4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine,1,8-diazabicylo[5.4.0]undec-7-ene, in a solvent such as toluene,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, acetonitrile,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone,water, methanol, ethanol, isopropanol, dimethyl sulfoxide, or mixturesthereof, at 20 to 220° C. by conventional or microwave heating.Alternatively, the piperidine 18 may be transformed into thecorresponding metal piperidide by deprotonation with a strong base, e.g.butyl lithium, NaH, or KH, prior to the addition of the electrophile 19.

Alternatively, residue R¹ may be attached to the N in compound 18 byreductive alkylation employing R¹ as aldehyde and a reducing agent, suchas NaH₃BCN or NaHB(O₂CCH₃)₃, or via a two step sequence by attaching acarboxylic acid derivative of R¹ first and reducing subsequently theresulting carboxamide.

The synthetic routes presented may rely on the use of protecting groups.For example, potentially reactive groups present, such as hydroxy,carbonyl, carboxy, amino, alkylamino, or imino, may be protected duringthe reaction by conventional protecting groups which are cleaved againafter the reaction. Suitable protecting groups for the respectivefunctionalities and their removal are well known to the one skilled inthe art and are described in the literature of organic synthesis.

The compounds of general formula I may be resolved into theirenantiomers and/or diastereomers as mentioned before. Thus, for example,cis/trans mixtures may be resolved into their cis and trans isomers andracemic compounds may be separated into their enantiomers.

The cis/trans mixtures may be resolved, for example, by chromatographyinto the cis and trans isomers thereof. The compounds of general formulaI which occur as racemates may be separated by methods known per se intotheir optical antipodes and diastereomeric mixtures of compounds ofgeneral formula I may be resolved into their diastereomers by takingadvantage of their different physico-chemical properties using methodsknown per se, e.g. chromatography and/or fractional crystallization; ifthe compounds obtained thereafter are racemates, they may be resolvedinto the enantiomers as mentioned above.

The racemates are preferably resolved by column chromatography on chiralphases or by crystallization from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as esters or amides with the racemic compound. Saltsmay be formed with enantiomerically pure acids for basic compounds andwith enantiomerically pure bases for acidic compounds. Diastereomericderivatives are formed with enantiomerically pure auxiliary compounds,e.g. acids, their activated derivatives, or alcohols. Separation of thediastereomeric mixture of salts or derivatives thus obtained may beachieved by taking advantage of their different physico-chemicalproperties, e.g. differences in solubility; the free antipodes may bereleased from the pure diastereomeric salts or derivatives by the actionof suitable agents. Optically active acids in common use for such apurpose are e.g. the D- and L-forms of tartaric acid, dibenzoyltartaricacid, ditoluoyltartaric acid, malic acid, mandelic acid, camphorsulfonicacid, glutamic acid, aspartic acid, or quinic acid. Optically activealcohols applicable as auxiliary residues may be, for example, (+) or(−)-menthol and optically active acyl groups in amides may be, forexample, (+)- or (−)-menthyloxycarbonyl.

As mentioned above, the compounds of formula I may be converted intosalts, particularly for pharmaceutical use into the pharmaceuticallyacceptable salts. As used herein, “pharmaceutically acceptable salts”refer to derivatives of the disclosed compounds wherein the parentcompound is modified by making acid or base salts thereof.

The compounds according to the invention are advantageously alsoobtainable using the methods described in the examples that follow,which may also be combined for this purpose with methods known to theskilled man from the literature.

TERMS AND DEFINITIONS

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

The terms “compound(s) according to this invention”, “compound(s) offormula (I)”, “compound(s) of the invention” and the like denote thecompounds of the formula (I) according to the present inventionincluding their tautomers, stereoisomers and mixtures thereof and thesalts thereof, in particular the pharmaceutically acceptable saltsthereof, and the solvates and hydrates of such compounds, including thesolvates and hydrates of such tautomers, stereoisomers and saltsthereof.

The terms “treatment” and “treating” embraces both preventative, i.e.prophylactic, or therapeutic, i.e. curative and/or palliative,treatment. Thus the terms “treatment” and “treating” comprisetherapeutic treatment of patients having already developed saidcondition, in particular in manifest form. Therapeutic treatment may besymptomatic treatment in order to relieve the symptoms of the specificindication or causal treatment in order to reverse or partially reversethe conditions of the indication or to stop or slow down progression ofthe disease. Thus the compositions and methods of the present inventionmay be used for instance as therapeutic treatment over a period of timeas well as for chronic therapy. In addition the terms “treatment” and“treating” comprise prophylactic treatment, i.e. a treatment of patientsat risk to develop a condition mentioned hereinbefore, thus reducingsaid risk.

When this invention refers to patients requiring treatment, it relatesprimarily to treatment in mammals, in particular humans.

The term “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease or condition, (ii) attenuates, ameliorates, oreliminates one or more symptoms of the particular disease or condition,or (iii) prevents or delays the onset of one or more symptoms of theparticular disease or condition described herein.

The terms “modulated” or “modulating”, or “modulate(s)”, as used herein,unless otherwise indicated, refers to the activation of theG-protein-coupled receptor GPR119 with one or more compounds of thepresent invention.

The terms “mediated” or “mediating” or “mediate”, as used herein, unlessotherwise indicated, refers to the (i) treatment, including preventionof the particular disease or condition, (ii) attenuation, amelioration,or elimination of one or more symptoms of the particular disease orcondition, or (iii) prevention or delay of the onset of one or moresymptoms of the particular disease or condition described herein.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom, radical or moiety is replaced with aselection from the indicated group, provided that the atom's normalvalence is not exceeded, and that the substitution results in anacceptably stable compound.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the last named subgroup isthe radical attachment point, for example, the substituent“aryl-C₁₋₃-alkyl-” means an aryl group which is bound to aC₁₋₃-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail.

An asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

The numeration of the atoms of a substituent starts with the atom whichis closest to the core or to the group to which the substituent isattached.

For example, the term “3-carboxypropyl-group” represents the followingsubstituent:

wherein the carboxy group is attached to the third carbon atom of thepropyl group.

The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or“cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

In a definition of a group the term “wherein each X, Y and Z group isoptionally substituted with” and the like denotes that each group X,each group Y and each group Z either each as a separate group or each aspart of a composed group may be substituted as defined. For example adefinition “R^(ex) denotes H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyl or C₁₋₃-alkyl-O—, wherein each alkyl group isoptionally substituted with one or more L^(ex).” or the like means thatin each of the beforementioned groups which comprise the term alkyl,i.e. in each of the groups C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl andC₁₋₃-alkyl-O—, the alkyl moiety may be substituted with L^(ex) asdefined.

In the following the term bicyclic includes spirocyclic.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc. . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts) also comprise a part of the invention.

The term halogen generally denotes fluorine, chlorine, bromine andiodine.

The term “C_(1-n)-alkyl”, wherein n is an integer from 1 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(1-n)-alkylene” wherein n is an integer 1 to n, either aloneor in combination with another radical, denotes an acyclic, straight orbranched chain divalent alkyl radical containing from 1 to n carbonatoms. For example the term C₁₋₄-alkylene includes —(CH₂)—, —(CH₂—CH₂)—,—(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—,—(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—,—(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—,—(CH₂—C(CH₃)₂)—, —(C(CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—,—(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—,—(CHCH(CH₃)₂)— and —C(CH₃)(CH₂CH₃)—.

The term “C_(2-n)-alkenyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenyl includes —CH═CH₂,—CH═CH—CH₃, —CH₂—CH═CH₂.

The term “C_(2-n)-alkenylene” is used for a group as defined in thedefinition for “C_(1-n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenylene includes —CH═CH—,—CH═CH—CH₂—, —CH₂—CH═CH—.

The term “C_(2-n)-alkynyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynyl includes —C≡CH,—C≡C—CH₃, —CH₂—C≡CH.

The term “C_(2-n)-alkynylene” is used for a group as defined in thedefinition for “C_(1-n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynylene includes —C≡C—,—C≡C—CH₂—, —CH₂—C≡C—.

The term “C_(3-n)-carbocyclyl” as used either alone or in combinationwith another radical, denotes a monocyclic, bicyclic or tricyclic,saturated or unsaturated hydrocarbon radical with 3 to n C atoms. Thehydrocarbon radical is preferably nonaromatic. Preferably the 3 to n Catoms form one or two rings. In case of a bicyclic or tricyclic ringsystem the rings may be attached to each other via a single bond or maybe fused or may form a spirocyclic or bridged ring system. For examplethe term C₃₋₁₀-carbocyclyl includes C₃₋₁₀-cylcoalkyl,C₃₋₁₀-cycloalkenyl, octahydropentalenyl, octahydroindenyl,decahydronaphthyl, indanyl, tetrahydronaphthyl. Most preferably the termC_(3-n)-carbocyclyl denotes C_(3-n)-cylcoalkyl, in particularC₃₋₇-cycloalkyl.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer from 4 to n,either alone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Thecyclic group may be mono-, bi-, tri- or spirocyclic, most preferablymonocyclic. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclododecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl,norpinyl, norbonyl, norcaryl, adamantyl, etc.

The term “C_(3-n)-cycloalkenyl”, wherein n is an integer from 4 to n,either alone or in combination with another radical, denotes a cyclic,unsaturated but nonaromatic, unbranched hydrocarbon radical with 3 to nC atoms, at least two of which are bonded to each other by a doublebond. For example the term C₃₋₇-cycloalkenyl includes cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl, cycloheptadienyl and cycloheptatrienyl.

The term “aryl” as used herein, either alone or in combination withanother radical, denotes a carbocyclic aromatic monocyclic groupcontaining 6 carbon atoms which may be further fused to a second 5- or6-membered carbocyclic group which may be aromatic, saturated orunsaturated. Aryl includes, but is not limited to, phenyl, indanyl,indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl anddihydronaphthyl. More preferably the term “aryl” as used herein, eitheralone or in combination with another radical, denotes phenyl ornaphthyl, most preferably phenyl.

The term “heterocyclyl” means a saturated or unsaturated mono-, bi-,tri- or spirocarbocyclic, preferably mono-, bi- or spirocyclic-ringsystem containing one or more heteroatoms selected from N, O or S(O)_(r)with r=0, 1 or 2, which in addition may have a carbonyl group. Morepreferably the term “heterocyclyl” as used herein, either alone or incombination with another radical, means a saturated or unsaturated, evenmore preferably a saturated mono-, bi- or spirocyclic-ring systemcontaining 1, 2, 3 or 4 heteroatoms selected from N, O or S(O)_(r) withr=0, 1 or 2 which in addition may have a carbonyl group. The term“heterocyclyl” is intended to include all the possible isomeric forms.Examples of such groups include aziridinyl, oxiranyl, azetidinyl,oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl,tetrahydropyranyl, azepanyl, piperazinyl, morpholinyl,tetrahydrofuranonyl, tetrahydropyranonyl, pyrrolidinonyl, piperidinonyl,piperazinonyl, and morpholinonyl.

Thus, the term “heterocyclyl” includes the following exemplarystructures which are not depicted as radicals as each form may beattached through a covalent bond to any atom so long as appropriatevalences are maintained:

The term “heteroaryl” means a mono- or polycyclic, preferably mono- orbicyclic ring system containing one or more heteroatoms selected from N,O or S(O)_(r) with r=0, 1 or 2 wherein at least one of the heteroatomsis part of an aromatic ring, and wherein said ring system may have acarbonyl group. More preferably the term “heteroaryl” as used herein,either alone or in combination with another radical, means a mono- orbicyclic-ring system containing 1, 2, 3 or 4 heteroatoms selected fromN, O or S(O)_(r) with r=0, 1 or 2 wherein at least one of theheteroatoms is part of an aromatic ring, and wherein said ring systemmay have a carbonyl group. The term “heteroaryl” is intended to includeall the possible isomeric forms.

Thus, the term “heteroaryl” includes the following exemplary structureswhich are not depicted as radicals as each form may be attached througha covalent bond to any atom so long as appropriate valences aremaintained:

Many of the terms given above may be used repeatedly in the definitionof a formula or group and in each case have one of the meanings givenabove, independently of one another.

Pharmacological Activity

The activity of the compounds of the invention may be demonstrated usingthe following assay:

The compounds of formula I according to the invention modulate theactivity of the G-protein-coupled receptor GPR119. The effect of thecompounds on the activation of GPR119 and on the stimulation ofintracellular cAMP concentration is determined using the AlphaScreencAMP Assay Kit (Cat. No. #6760625R) made by PerkinElmer.

MIN6 cells [Miyazaki J et al. Endocrinology. 1990 July; 127(1):126-32]are stably transfected with an expression vector for human GPR119 cDNA(Acc. No. NP_(—)848566). Min-6/hGPR119 cells are cultured in DMEM, 10%FBS, 50 μM β-mercaptoethanol, 0.3 mg/mL Geniticin, 2 mM GlutaMAX at 37°C. 5% CO₂. For the assay, the cells are seeded in Optiplates (white,384-well, 160W-barcoded, TC, sterile with lid, Cat. No. #6007688 (PerkinElmer); 10000 cells/well; 50 μl). The plates covered with lids are thenincubated for 24 hours at 37° C./5% CO₂. After the medium is aspiratedfrom the wells completely, 10 μl of the test compound are added, thecompounds are diluted using stimulating buffer (140 mM NaCl, 3.6 mM KCl,0.5 mM NaH₂PO₄, 0.5 mM MgSO₄, 1.5 mM CaCl₂, 10 mM Hepes, 5 mM NaHCO₃; pH7.4. 0.5 mM IBMX and 0.1% BSA, the final DMSO concentration is 1%).After 45 minutes incubation at room temperature (approx. 20° C.), thecAMP concentrations are determined using the AlphaScreen cAMP Assay Kit(Cat. No. #6760625R from PerkinElmer). 10 μl of Biotin-cAMP (finalconcentration 1 U/well in lysing buffer (5 mM Hepes (pH 7.4), 0.1% BSA,0.5% Tween) and 10 μL Bead solution (final concentration 1 U/well inlysing buffer) are added. The plates are incubated for another 2 hoursat room temperature. The cAMP concentrations are calculated using a cAMPstandard curve from the Alpha Screen Counts. The data analysis iscarried out by calculating the EC50 value and the maximum value based ona positive control, using suitable software (Graphpad Prism). Thecompounds according to the invention increase the intracellular cAMPlevel in the range of 3-5.

The compounds according to the invention typically have EC₅₀ values inthe range from about 1 nM to about 10 μM, preferably less than 1 μM,more preferably less than 500 nM, most preferably less than 100 nM.

EC₅₀ values for compounds according to the invention are shown in thefollowing Table. The number of the compound corresponds to the number ofthe Example in the experimental section.

Exam- EC₅₀ Exam- EC₅₀ Exam- EC₅₀ Exam- EC₅₀ ple [nM] ple [nM] ple [nM]ple [nM] 1 417 2 25 3 36 4 215 5 663 6 21 7 22 8 35 9 100 10 66 11 84812 46 13 5 14 2 15 78 16 25 17 25 18 27 19 84

In view of their ability to modulate the activity of theG-protein-coupled receptor GPR119, in particular an agonistic activity,the compounds of general formula (I) according to the invention,including the corresponding salts thereof, are theoretically suitablefor the treatment of all those diseases or conditions which may beaffected or which are mediated by the activation of theG-protein-coupled receptor GPR119.

Accordingly, the present invention relates to a compound of generalformula (I) as a medicament.

Furthermore, the present invention relates to the use of a compound ofgeneral formula (I) or a pharmaceutical composition according to thisinvention for the treatment and/or prevention of diseases or conditionswhich are mediated by the activation of the G-protein-coupled receptorGPR119 in a patient, preferably in a human.

In yet another aspect the present invention relates to a method fortreating a disease or condition mediated by the activation of theG-protein-coupled receptor GPR119 in a mammal that includes the step ofadministering to a patient, preferably a human, in need of suchtreatment a therapeutically effective amount of a compound or apharmaceutical composition of the present invention.

Diseases and conditions mediated by agonists of the G-protein-coupledreceptor GPR119 embrace metabolic diseases or conditions.

According to one aspect the compounds and pharmaceutical compositions ofthe present invention are particularly suitable for treating diabetesmellitus, in particular Type 2 diabetes, Type 1 diabetes, complicationsof diabetes (such as e.g. retinopathy, nephropathy or neuropathies,diabetic foot, ulcers or macro-angiopathies), metabolic acidosis orketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose metabolicdisorder, insulin resistance, metabolic syndrome, dyslipidaemias ofdifferent origins, atherosclerosis and related diseases, obesity, highblood pressure, chronic heart failure, oedema and hyperuricaemia.

The compounds and pharmaceutical compositions of the present inventionare also suitable for preventing beta-cell degeneration such as e.g.apoptosis or necrosis of pancreatic beta cells. The compounds andpharmaceutical compositions of the present invention are also suitablefor improving or restoring the functionality of pancreatic cells, andalso for increasing the number and size of pancreatic beta cells.

Therefore according to another aspect the invention relates to compoundsof formula I and pharmaceutical compositions according to the inventionfor use in preventing, delaying, slowing the progression of and/ortreating metabolic diseases, particularly in improving the glycaemiccontrol and/or beta cell function in the patient.

In another aspect the invention relates to compounds of formula I andpharmaceutical compositions according to the invention for use inpreventing, delaying, slowing the progression of and/or treating type 2diabetes, overweight, obesity, complications of diabetes and associatedpathological conditions.

In addition the compounds and pharmaceutical compositions according tothe invention are suitable for use in one or more of the followingtherapeutic processes:

-   -   for preventing, delaying, slowing the progression of or treating        metabolic diseases, such as for example type 1 diabetes, type 2        diabetes, insufficient glucose tolerance, insulin resistance,        hyperglycaemia, hyperlipidaemia, hypercholesterolaemia,        dyslipidaemia, syndrome X, metabolic syndrome, obesity, high        blood pressure, chronic systemic inflammation, retinopathy,        neuropathy, nephropathy, atherosclerosis, endothelial        dysfunction or bone-related diseases (such as osteoporosis,        rheumatoid arthritis or osteoarthritis);    -   for improving glycaemic control and/or reducing fasting plasma        glucose, postprandial plasma glucose and/or the glycosylated        haemoglobin HbA1c;    -   for preventing, delaying, slowing or reversing the progression        of disrupted glucose tolerance, insulin resistance and/or        metabolic syndrome to type 2 diabetes;    -   for preventing, delaying, slowing the progression of or treating        a condition or a disease selected from among the complications        of diabetes, such as for example retinopathy, nephropathy or        neuropathies, diabetic foot, ulcers or macroangiopathies;    -   for reducing weight or preventing weight gain or assisting        weight loss;    -   for preventing or treating the degradation of pancreatic beta        cells and/or improving and/or restoring the functionality of        pancreatic beta cells and/or restoring the functionality of        pancreatic insulin secretion;    -   for maintaining and/or improving insulin sensitivity and/or        preventing or treating hyperinsulinaemia and/or insulin        resistance.

In particular, the compounds and pharmaceutical compositions accordingto the invention are suitable for the treatment of obesity, diabetes(comprising type 1 and type 2 diabetes, preferably type 2 diabetesmellitus) and/or complications of diabetes (such as for exampleretinopathy, nephropathy or neuropathies, diabetic foot, ulcers ormacroangiopathies).

The compounds according to the invention are most particularly suitablefor treating type 2 diabetes mellitus.

The dose range of the compounds of general formula (I) applicable perday is usually from 0.001 to 10 mg per kg body weight, for example from0.01 to 8 mg per kg body weight of the patient. Each dosage unit mayconveniently contain from 0.1 to 1000 mg, for example 0.5 to 500 mg.

The actual therapeutically effective amount or therapeutic dosage willof course depend on factors known by those skilled in the art such asage and weight of the patient, route of administration and severity ofdisease. In any case the compound or composition will be administered atdosages and in a manner which allows a therapeutically effective amountto be delivered based upon patient's unique condition.

The compounds, compositions, including any combinations with one or moreadditional therapeutic agents, according to the invention may beadministered by oral, transdermal, inhalative, parenteral or sublingualroute. Of the possible methods of administration, oral or intravenousadministration is preferred.

Pharmaceutical Compositions

Suitable preparations for administering the compounds of formula (I),optionally in combination with one or more further therapeutic agents,will be apparent to those with ordinary skill in the art and include forexample tablets, pills, capsules, suppositories, lozenges, troches,solutions, syrups, elixirs, sachets, injectables, inhalatives andpowders etc. Oral formulations, particularly solid forms such as e.g.tablets or capsules are preferred. The content of the pharmaceuticallyactive compound(s) is advantageously in the range from 0.1 to 90 wt.-%,for example from 1 to 70 wt.-% of the composition as a whole.

Suitable tablets may be obtained, for example, by mixing one or morecompounds according to formula (I) with known excipients, for exampleinert diluents, carriers, disintegrants, adjuvants, surfactants, bindersand/or lubricants. The tablets may also consist of several layers. Theparticular excipients, carriers and/or diluents that are suitable forthe desired preparations will be familiar to the skilled man on thebasis of his specialist knowledge. The preferred ones are those that aresuitable for the particular formulation and method of administrationthat are desired. The preparations or formulations according to theinvention may be prepared using methods known per se that are familiarto the skilled man, such as for example by mixing or combining at leastone compound of formula I according to the invention, or apharmaceutically acceptable salt of such a compound, and one or moreexcipients, carriers and/or diluents.

Combination Therapy

The compounds of the invention may further be combined with one or more,preferably one additional therapeutic agent. According to one embodimentthe additional therapeutic agent is selected from the group oftherapeutic agents useful in the treatment of diseases or conditionsdescribed hereinbefore, in particular associated with metabolic diseasesor conditions such as for example diabetes mellitus, obesity, diabeticcomplications, hypertension, hyperlipidemia. Additional therapeuticagents which are suitable for such combinations include in particularthose which for example potentiate the therapeutic effect of one or moreactive substances with respect to one of the indications mentionedand/or which allow the dosage of one or more active substances to bereduced.

Therefore a compound of the invention may be combined with one or moreadditional therapeutic agents selected from the group consisting ofantidiabetic agents, agents for the treatment of overweight and/orobesity and agents for the treatment of high blood pressure, heartfailure and/or atherosclerosis.

Antidiabetic agents are for example metformin, sulphonylureas,nateglinide, repaglinide, thiazolidinediones, PPAR-(alpha, gamma oralpha/gamma) agonists or modulators, alpha-glucosidase inhibitors, DPPIVinhibitors, SGLT2-inhibitors, insulin and insulin analogues, GLP-1 andGLP-1 analogues or amylin and amylin analogues, cycloset, 11β-HSDinhibitors. Other suitable combination partners are inhibitors ofprotein tyrosinephosphatase 1, substances that affect deregulatedglucose production in the liver, such as e.g. inhibitors ofglucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogenphosphorylase, glucagon receptor antagonists and inhibitors ofphosphenol pyruvate carboxykinase, glycogen synthase kinase or pyruvatedehydrokinase, alpha2-antagonists, CCR-2 antagonists or glucokinaseactivators. One or more lipid lowering agents are also suitable ascombination partners, such as for example HMG-CoA-reductase inhibitors,fibrates, nicotinic acid and the derivatives thereof, PPAR-(alpha, gammaor alpha/gamma) agonists or modulators, PPAR-delta agonists, ACATinhibitors or cholesterol absorption inhibitors such as, bileacid-binding substances such as, inhibitors of ileac bile acidtransport, MTP inhibitors, or HDL-raising compounds such as CETPinhibitors or ABC1 regulators.

Therapeutic agents for the treatment of overweight and/or obesity arefor example antagonists of the cannabinoid1 receptor, MCH-1 receptorantagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists,β3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor.

Therapeutic agents for the treatment of high blood pressure, chronicheart failure and/or atherosclerosis are for example A-II antagonists orACE inhibitors, ECE inhibitors, diuretics, β-blockers, Ca-antagonists,centrally acting antihypertensives, antagonists of thealpha-2-adrenergic receptor, inhibitors of neutral endopeptidase,thrombocyte aggregation inhibitors and others or combinations thereofare suitable. Angiotensin II receptor antagonists are preferably usedfor the treatment or prevention of high blood pressure and complicationsof diabetes, often combined with a diuretic such as hydrochlorothiazide.

The dosage for the combination partners mentioned above is usually ⅕ ofthe lowest dose normally recommended up to 1/1 of the normallyrecommended dose.

Preferably, compounds of the present invention and/or pharmaceuticalcompositions comprising a compound of the present invention optionallyin combination with one or more additional therapeutic agents areadministered in conjunction with exercise and/or a diet.

Therefore, in another aspect, this invention relates to the use of acompound according to the invention in combination with one or moreadditional therapeutic agents described hereinbefore and hereinafter forthe treatment of diseases or conditions which may be affected or whichare mediated by the activation of the G-protein-coupled receptor GPR119,in particular diseases or conditions as described hereinbefore andhereinafter.

In yet another aspect the present invention relates a method fortreating a disease or condition mediated by the activation of theG-protein-coupled receptor GPR119 in a patient that includes the step ofadministering to the patient, preferably a human, in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention in combination with a therapeutically effective amountof one or more additional therapeutic agents described in hereinbeforeand hereinafter.

The use of the compound according to the invention in combination withthe additional therapeutic agent may take place simultaneously or atstaggered times.

The compound according to the invention and the one or more additionaltherapeutic agents may both be present together in one formulation, forexample a tablet or capsule, or separately in two identical or differentformulations, for example as a so-called kit-of-parts.

Consequently, in another aspect, this invention relates to apharmaceutical composition which comprises a compound according to theinvention and one or more additional therapeutic agents describedhereinbefore and hereinafter, optionally together with one or more inertcarriers and/or diluents.

Other features and advantages of the present invention will becomeapparent from the following more detailed Examples which illustrate, byway of example, the principles of the invention.

EXAMPLES

The terms “ambient temperature” and “room temperature” are usedinterchangeably and designate a temperature of about 20° C.

Preliminary Remarks:

As a rule, ¹H-NMR and/or mass spectra have been obtained for thecompounds prepared. The R_(f) values are determined using Merck silicagel 60 F₂₅₄ plates and UV light at 254 nm or staining withphosphomolybdic acid.

Analytical HPLC parameters employed for characterization of products(TFA denotes trifluoroacetic acid):

method 1 column Waters XBridge C18, 4.6 × 30 mm, 3.5 μm mobile phase A:water + 0.1% formic acid B: methanol TIME (min) A % B % 0.0 95 5 0.15 955 1.70 0 100 2.25 0 100 flow rate 4.0 mL/min wavelength UV 220, 230, or254 nm method 2 column Waters XBridge C18, 3 × 30 mm, 2.5 μm mobilephase A: water + 0.1% NH₄OH B: methanol TIME (min) A % B % 0.0 95 5 0.0595 5 1.40 0 100 1.80 0 100 flow rate 2.2 mL/min wavelength UV 220, 230,or 254 nm method 3 column Waters XBridge C18, 4.6 × 30 mm, 3.5 μm mobilephase A: water + 0.1% TFA B: methanol TIME (min) A % B % 0.0 95 5 1.60 0100 1.85 0 100 1.90 95 5 flow rate 4.0 mL/min wavelength UV 220, 230, or254 nm method 4 column Waters XBridge C18, 3 × 30 mm, 2.5 μm mobilephase A: water + 0.1% TFA B: methanol TIME (min) A % B % 0.0 95 5 0.0595 5 1.40 0 100 1.80 0 100 flow rate 2.2 mL/min wavelength UV 220, 230,or 254 nm

Intermediate 14-(5-Bromo-2-hydroxy-phenylethynyl)-piperidine-1-carboxylic acidtert-butyl ester

A mixture of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester(4.03 g), 4-bromo-2-iodo-phenol (5.00 g), Pd(PPh₃)₂Cl₂ (600 mg), copperiodide (500 mg), and triethylamine (2.35 mL) in N,N-dimethylformamide(30 mL) is heated under an argon atmosphere to 75° C. for 4 h. Thereaction mixture is diluted with ice water after cooling to roomtemperature and extracted with ethyl acetate. The combined extracts aredried over MgSO₄ and concentrated in vacuo. The residue ischromatographed on silica gel (cyclohexane/ethyl acetate 80:20→60:40) togive the title compound. LC (method 2): t_(R)=1.32 min; Mass spectrum(ESI⁺): m/z=402, 404 [M+Na]⁺.

Intermediate 2 4-(5-Bromo-benzofuran-2-yl)-piperidine-1-carboxylic acidtert-butyl ester

A mixture of 4-(5-bromo-2-hydroxy-phenylethynyl)-piperidine-1-carboxylicacid tert-butyl ester (70 mg), copper iodide (9 mg),N,N-dimethylformamide (1 mL), triethylamine (100 μL), and Pd(PPh₃)₂Cl₂(7 mg) is heated under an argon atmosphere to 55° C. for 0.5 h. Thereaction mixture is diluted with ice water after cooling to roomtemperature and extracted with ethyl acetate. The combined extracts aredried over MgSO₄ and concentrated in vacuo. The residue ischromatographed on silica gel (cyclohexane/ethyl acetate 80:20→50:50) togive the title compound. LC (method 2): t_(R)=1.49 min; Mass spectrum(ESI⁺): m/z=380, 382 [M+H]⁺.

Intermediate 34-[5-(4-Methanesulfonyl-phenyl)-benzofuran-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

An aqueous Na₂CO₃ solution (2 M, 0.68 mL) is added to a mixture of4-(5-bromo-benzofuran-2-yl)-piperidine-1-carboxylic acid tert-butylester (2.50 g) and 4-(methanesulfonyl)phenylboronic acid (1.97 g) in amixture of dioxane/water (60:40). The mixture is sparged with argon for10 min and PdCl_(2[)1,1′-bis(diphenylphosphino)-ferrocene]*CH₂Cl₂complex (500 mg) is added. The resulting mixture is heated to 100° C.for 2 h. After cooling to room temperature, ethyl acetate, brine, andactivated charcoal are added. The mixture is filtered and the organicphase is separated, dried over Na₂SO₄, and the solvent is evaporated.The residue is chromatographed on silica gel (cyclohexane/ethyl acetate80:20→60:40) to give the title compound. LC (method 1): t_(R)=1.80 min;Mass spectrum (ESI⁺): m/z=478 [M+Na]⁺.

Intermediate 44-[5-(4-Methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

A mixture of4-[5-(4-methanesulfonyl-phenyl)-benzofuran-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (1.70 g), 10% palladium on carbon (200 mg),ethanol (100 mL), and ethyl acetate (50 mL) is shaken under hydrogenatmosphere (5 bar) at 45° C. until the starting material is completelyconsumed. The catalyst is filtered off, the filtrate is concentrated invacuo, and the residue is chromatographed on silica gel(cyclohexane/ethyl acetate/methanol 70:30:0→50:40:10) to give the titlecompound. LC (method 1): t_(R)=1.75 min; Mass spectrum (ESI⁺): m/z=458[M+H]⁺.

Intermediate 54-[5-(4-Methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine

A solution of HCl in dioxane (4 N, 5.0 mL) is added to4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (750 mg) in dichloromethane (1 mL) and theresulting mixture is stirred for 5 min at room temperature. The solventsare evaporated in vacuo to give the title compound as its hydrochloricacid salt. Mass spectrum (ESI⁺): m/z=358 [M+H]⁺.

Intermediate 61-{-4-[5-(4-Methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-2-methyl-propan-2-ol

A mixture of4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidinehydrochloride (100 mg) and N,N-diisopropylethylamine (46 μl) in methanol(5 mL) is stirred for 10 min at room temperature. 1,1-Dimethyloxirane(34 μl) is added and the resulting mixture is heated to 45° C. After theconversion is complete, the solvents are evaporated in vacuo and thecrude product is used for the next step without further purification. LC(method 1): t_(R)=1.09 min; Mass spectrum (ESI⁺): m/z=430 [M+H]⁺.

Intermediate 74-[2-(5-Bromo-2-chloro-pyridin-4-yl)-acetyl]-piperidine-1-carboxylicacid tert-butyl ester

Lithium bis(trimethylsilyl)amide solution (1.0 M in tetrahydrofuran;11.00 mL) is added dropwise to 5-bromo-2-chloro-4-picoline (950 mg) intetrahydrofuran (15 mL) at −40° C. under argon atmosphere. The mixtureis stirred for 2 h at −35° C. to −45° C. prior to the addition ofpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1.33g) dissolved in tetrahydrofuran (15 mL). The reaction mixture is allowedto warm to room temperature over a period of 1 h. Ice-cold water isadded and the mixture is extracted with ethyl acetate. The combinedextracts are washed with brine, dried over MgSO₄, and concentrated invacuo. The residue is chromatographed on silica gel (cyclohexane/ethylacetate 75:25→60:40) to give the title compound. LC (method 3):t_(R)=1.43 min; Mass spectrum (ESI⁺): m/z=417, 419 [M+H]⁺.

Intermediate 84-[2-(5-Bromo-2-chloro-pyridin-4-yl)-1-hydroxy-ethyl]-piperidine-1-carboxylicacid tert-butyl ester

Sodium borohydride (240 mg) is added to an ice-cooled solution of4-[2-(5-bromo-2-chloro-pyridin-4-yl)-acetyl]-piperidine-1-carboxylicacid tert-butyl ester (1.65 g) in a mixture of tetrahydrofuran (40 mL)and water (10 mL). The resulting mixture is stirred for 0.5 h at roomtemperature. 2 N Aqueous citric acid is added and the mixture isextracted with ethyl acetate. The combined extracts are washed withaqueous NaHCO₃ solution and brine, dried over MgSO₄, and concentrated invacuo. The residue is chromatographed on silica gel (cyclohexane/ethylacetate 65:35) to give the title compound. LC (method 3): t_(R)=1.48min; Mass spectrum (ESI⁺): m/z=419, 421 [M+H]⁺.

Intermediate 94-(5-Chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylicacid tert-butyl ester

A mixture of4-[2-(5-bromo-2-chloro-pyridin-4-yl)-1-hydroxy-ethyl]-piperidine-1-carboxylicacid tert-butyl ester (11.60 g), palladium acetate (500 mg), racemic2-(di-tert-butylphosphino)-1,1′-binaphthyl (1.00 g), and cesiumcarbonate (14.00 g) in toluene (150 mL) is heated in an oil bath at 110°C. under argon atmosphere for 5 h. After cooling to room temperature,ethyl acetate and water are added and the organic phase is separated,washed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue is chromatographed on silica gel (cyclohexane/ethyl acetate70:30→50:50) to give the title compound. LC (method 3): t_(R)=1.44 min;Mass spectrum (ESI⁺): m/z=339 [M+H]⁺.

Intermediate 104-[5-(4-Methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

A mixture of4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylicacid tert-butyl ester (400 mg), 4-(methanesulfonyl)phenyl boronic acid(321 mg), aqueous Na₂CO₃ solution (2 M; 1.60 mL), and dioxane (15 mL) issparged with argon for 10 min and Pd(PPh₃)₄ (100 mg) is added. Theresulting mixture is heated to 150° C. in a microwave oven until theconversion is complete. The reaction mixture is diluted with water andextracted with ethyl acetate. The organic phase is dried over MgSO₄ andthe solvent is evaporated. The residue is chromatographed on silica gel(cyclohexane/ethyl acetate 40:60→20:80) to give the title compound. LC(method 3): t_(R)=1.32 min; Mass spectrum (ESI⁺): m/z=459 [M+H]⁺.

Intermediate 115-(4-Methanesulfonyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine

A mixture of4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (190 mg) and trifluoroacetic acid (0.40 mL) indichloromethane (3 mL) is stirred at room temperature for 2 h. Thereaction mixture is diluted with dichloromethane and washed with aqueousNa₂CO₃ solution. The aqueous phase is extracted with dichloromethane andthe combined organic phases are washed with water, dried over MgSO₄, andconcentrated in vacuo. LC (method 3): t_(R)=0.62 min; Mass spectrum(ESI⁺): m/z=359 [M+H]⁺.

Intermediate 124-[5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylicacid tert-butyl ester and1-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridinefollowing a procedure analogous to that described for Intermediate 10.LC (method 3): t_(R)=1.12 min; Mass spectrum (ESI⁺): m/z=464 [M+H]⁺.

Intermediate 135-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester following a procedure analogous to that describedfor Intermediate 11. LC (method 3): t_(R)=0.44 min; Mass spectrum(ESI⁺): m/z=364 [M+H]⁺.

Intermediate 141-{4-[5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidin-1-yl}-2-methyl-propan-2-ol

The title compound is prepared from5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridinefollowing a procedure analogous to that described for Intermediate 6. LC(method 3): t_(R)=0.50 min; Mass spectrum (ESI⁺): m/z=436 [M+H]⁺.

Intermediate 154-[5-(4-Methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylicacid tert-butyl ester and 4-(methanesulfonylmethyl)phenyl boronic acidfollowing a procedure analogous to that described for Intermediate 10.LC (method 1): t_(R)=1.55 min; Mass spectrum (ESI⁺): m/z=473 [M+H]⁺.

Intermediate 165-(4-Methanesulfonylmethyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from4-[5-(4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester following a procedure analogous to that describedfor Intermediate 11. LC (method 1): t_(R)=0.73 min; Mass spectrum(ESI⁺): m/z=373 [M+H]⁺.

Intermediate 171-{4-[5-(4-Methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidin-1-yl}-2-methyl-propan-2-ol

The title compound is prepared from5-(4-methanesulfonylmethyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridinefollowing a procedure analogous to that described for Intermediate 6. LC(method 1): t_(R)=0.79 min; Mass spectrum (ESI⁺): m/z=445 [M+H]⁺.

Intermediate 184-[5-(2-Fluoro-4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylicacid tert-butyl ester and2-(2-fluoro-4-methanesulfonylmethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolanefollowing a procedure analogous to that described for Intermediate 10.LC (method 1): t_(R)=1.61 min; Mass spectrum (ESI⁺): m/z=491 [M+H]⁺.

Intermediate 195-(2-Fluoro-4-methanesulfonylmethyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from4-[5-(2-fluoro-4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester following a procedure analogous to that describedfor Intermediate 11. LC (method 1): t_(R)=0.78 min; Mass spectrum(ESI⁺): m/z=391 [M+H]⁺.

Intermediate 201-{4-[5-(2-Fluoro-4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidin-1-yl}-2-methyl-propan-2-ol

The title compound is prepared from5-(2-fluoro-4-methanesulfonylmethyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridinefollowing a procedure analogous to that described for Intermediate 6. LC(method 1): t_(R)=0.85 min; Mass spectrum (ESI⁺): m/z=463 [M+H]⁺.

Intermediate 214-[2-(5-Bromo-2-chloro-pyridin-4-yl)-1-hydroxy-1-methyl-ethyl]-piperidine-1-carboxylicacid tert-butyl ester

A solution of4-[2-(5-bromo-2-chloro-pyridin-4-yl)-acetyl]-piperidine-1-carboxylicacid tert-butyl ester (9.80 g) in tetrahydrofuran (6 mL) is addeddropwise to an ice cooled solution of methyl magnesium bromide (1.4 M intoluene/tetrahydrofuran 75:25, 74 mL). The reaction mixture is stirredfor 30 min in the cooling bath and then at room temperature for 1 h. Themixture is poured into aqueous NH₄Cl solution and extracted with ethylacetate. The combined extracts are dried over MgSO₄ and concentrated invacuo. Since the residue still contains a considerable amount ofstarting material, it is azeotropically dried using toluene andresubmitted to the procedure described above. The crude product ispurified by preparative HPLC (column: Waters X-Bridge C18; mobile phase:water+0.125% NH₄OH/methanol 90:10→100:0) to give the title compound. LC(method 4): t_(R)=1.33 min; Mass spectrum (ESI⁺): m/z=433, 435 [M+H]⁺.

Intermediate 224-(5-Chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from4-[2-(5-bromo-2-chloro-pyridin-4-yl)-1-hydroxy-1-methyl-ethyl]-piperidine-1-carboxylicacid tert-butyl ester following a procedure analogous to that describedfor Intermediate 9. LC (method 4): t_(R)=1.29 min; Mass spectrum (ESI⁺):m/z=353 [M+H]⁺.

Intermediate 23 and 24(S)-4-(5-Chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylicacid tert-butyl ester and(R)-4-(5-Chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylicacid tert-butyl ester

The title compounds are obtained in separate fractions upon SFC onchiral phase of racemic Intermediate 22 (column: Daicel IC, 250×20 mm;mobile phase: methanol containing 0.2% diethylamine/sc carbon dioxide25:75; flow rate 60 ml/min). The configurations of the stereocenters ofIntermediates 23 and 24 were unambiguously determined by X-ray analysisof the crystal structure of a derivative of Intermediate 23,(S)-2-[1-(5-bromo-pyrimidin-2-yl)-piperidin-4-yl]-5-chloro-2,3-dihydro-furo[2,3-c]pyridine(obtained upon acid induced liberation of the piperidine N ofIntermediate 23 and its subsequent derivatization with5-bromo-2-chloro-pyrimidine); retention times on the SFC on chiral phase(Daicel IC, 250×4.6 mm; mobile phase: methanol containing 0.2%diethylamine/sc carbon dioxide 25:75; flow rate 4 ml/min): Intermediate23: t_(R)=3.77 min; Intermediate 24: t_(R)=4.42 min.

Intermediate 25(R)-4-[5-(4-Methanesulfonyl-phenyl)-2-methyl-2,3-dihydro-furor[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from(S)-4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylicacid tert-butyl ester and 4-(methanesulfonyl)phenylboronic acidfollowing a procedure analogous to that described for Intermediate 10.LC (method 4): t_(R)=1.19 min; Mass spectrum (ESI⁺): m/z=473 [M+H]⁺.

Intermediate 26(R)-5-(4-Methanesulfonyl-phenyl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from(S)-4-[5-(4-methanesulfonyl-phenyl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester following a procedure analogous to that describedfor Intermediate 11. LC (method 4): t_(R)=0.63 min; Mass spectrum(ESI⁺): m/z=373 [M+H]⁺.

Intermediate 27(R)-1-{4-[5-(4-Methanesulfonyl-phenyl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidin-1-yl}-2-methyl-propan-2-ol

The title compound is prepared from(S)-5-(4-methanesulfonyl-phenyl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridinefollowing a procedure analogous to that described for Intermediate 6. LC(method 4): t_(R)=0.67 min; Mass spectrum (ESI⁺): m/z=445 [M+H]⁺.

Intermediate 28 and 29(R)-4-(5-Chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylicacid tert-butyl ester and(S)-4-(5-Chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylicacid tert-butyl ester

The title compounds are obtained in separate fractions upon SFC onchiral phase of racemic Intermediate 9 (column: Daicel IC, 250×20 mm;mobile phase: ethanol containing 0.2% diethylamine/sc carbon dioxide25:75; flow rate 50 ml/min). The configurations of the stereocenters ofIntermediates 28 and 29 were unambiguously determined by X-ray analysisof a crystal structure of Intermediate 29; retention times on the SFC onchiral phase (Daicel IC, 250×4.6 mm; mobile phase: ethanol containing0.2% diethylamine/sc carbon dioxide 25:75; flow rate 4 ml/min):Intermediate 28: t_(R)=1.64 min; Intermediate 29: t_(R)=1.91 min.

Intermediate 30(S)-4-[5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from(S)-4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylicacid tert-butyl ester and1-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridinefollowing a procedure analogous to that described for Intermediate 10.LC (method 3): t_(R)=1.10 min; Mass spectrum (ESI⁺): m/z=464 [M+H]⁺.

Intermediate 31

(S)-5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from(S)-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester following a procedure analogous to that describedfor Intermediate 11. LC (method 3): t_(R)=0.44 min; Mass spectrum(ESI⁺): m/z=364 [M+H]⁺.

Intermediate 32(S)-1-{4-[5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidin-1-yl}-2-methyl-propan-2-ol

The title compound is prepared from(S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridinefollowing a procedure analogous to that described for Intermediate 6. LC(method 3): t_(R)=0.50 min; Mass spectrum (ESI⁺): m/z=436 [M+H]⁺.

Intermediate 33(R)-4-[5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from(R)-4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylicacid tert-butyl ester and1-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridinefollowing a procedure analogous to that described for Intermediate 10.LC (method 3): t_(R)=1.10 min; Mass spectrum (ESI⁺): m/z=464 [M+H]⁺.

Intermediate 34(R)-5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from(R)-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester following a procedure analogous to that describedfor Intermediate 11. LC (method 3): t_(R)=0.44 min; Mass spectrum(ESI⁺): m/z=364 [M+H]⁺.

Intermediate 35(R)-1-{4-[5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidin-1-yl}-2-methyl-propan-2-ol

The title compound is prepared from(R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridinefollowing a procedure analogous to that described for Intermediate 6. LC(method 3): t_(R)=0.50 min; Mass spectrum (ESI⁺): m/z=436 [M+H]⁺.

Intermediate 36(R)-4-[5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from(S)-4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylicacid tert-butyl ester and1-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridinefollowing a procedure analogous to that described for Intermediate 10.LC (method 4): t_(R)=1.02 min; Mass spectrum (ESI⁺): m/z=478 [M+H]⁺.

Intermediate 37(R)-5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from(S)-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester following a procedure analogous to that describedfor Intermediate 11. LC (method 4): t_(R)=0.48 min; Mass spectrum(ESI⁺): m/z=378 [M+H]⁺.

Intermediate 38(R)-1-{4-[5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidin-1-yl}-2-methyl-propan-2-ol

The title compound is prepared from(S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridinefollowing a procedure analogous to that described for Intermediate 6. LC(method 4): t_(R)=0.55 min; Mass spectrum (ESI⁺): m/z=450 [M+H]⁺.

Intermediate 39(R)-4-[5-(4-Methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from(R)-4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylicacid tert-butyl ester and 4-(methanesulfonyl)phenylboronic acidfollowing a procedure analogous to that described for Intermediate 10.LC (method 1): t_(R)=1.68 min; Mass spectrum (ESI⁺): m/z=459 [M+H]⁺.

Intermediate 40(R)-5-(4-Methanesulfonyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from(R)-4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester following a procedure analogous to that describedfor Intermediate 11. LC (method 1): t_(R)=0.90 min; Mass spectrum(ESI⁺): m/z=359 [M+H]⁺.

Intermediate 41(R)-1-{4-[5-(4-Methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidin-1-yl}-2-methyl-propan-2-ol

The title compound is prepared from(R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridinefollowing a procedure analogous to that described for Intermediate 6. LC(method 1): t_(R)=0.91 min; Mass spectrum (ESI⁺): m/z=431 [M+H]⁺.

Example 11-(2-Fluoro-2-methyl-propyl)-4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine

A solution of [bis(2-methoxyethyl)amino]sulfur trifluoride in toluene(50%; 162 μL) is added to an ice-cooled solution of1-{4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-2-methyl-propan-2-ol(100 mg) in dichloromethane (2 mL) and the resulting mixture is stirredfor 16 h. The reaction mixture is diluted with methanol and concentratedin vacuo. The residue is purified by HPLC to give the title compound. LC(method 1): t_(R)=1.17 min; Mass spectrum (ESI⁺): m/z=432 [M+H]⁺.

Example 25-(4-Methanesulfonyl-phenyl)-2-{1-[(1-trifluoromethyl-cyclopropyl)methyl]-piperidin-4-yl}-2,3-dihydro-furo[2,3-c]pyridine

A mixture of5-(4-methanesulfonyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine(435 mg), methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methylester (700 mg), potassium carbonate (850 mg), and potassium iodide (100mg) in N-methyl-2-pyrrolidone (8 mL) is stirred at 100° C. for 4 h andthen at room temperature overnight. The solvent is evaporated and theresidue is triturated with methanol and filtered. The filtrate isconcentrated in vacuo and the residue is purified by HPLC to give thetitle compound. LC (method 1): t_(R)=1.09 min; Mass spectrum (ESI⁺):m/z=481 [M+H]⁺.

Example 32-[1-(2-Fluoro-2-methyl-propyl)-piperidin-4-yl]-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from1-{4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidin-1-yl}-2-methyl-propan-2-olfollowing a procedure analogous to that described in Example 1. LC(method 3): t_(R)=0.62 min; Mass spectrum (ESI⁺): m/z=438 [M+H]⁺.

Example 42-[1-(2-Fluoro-2-methyl-propyl)-piperidin-4-yl]-5-(4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from1-{4-[5-(4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidin-1-yl}-2-methyl-propan-2-olfollowing a procedure analogous to that described in Example 1. LC(method 1): t_(R)=0.86 min; Mass spectrum (ESI⁺): m/z=447 [M+H]⁺.

Example 52-[1-(2-Fluoro-2-methyl-propyl)-piperidin-4-yl]-5-(1-methanesulfonyl-piperidin-4-yl)-2,3-dihydro-furo[2,3-c]pyridine

A mixture of2-[1-(2-fluoro-2-methyl-propyl)-piperidin-4-yl]-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridine(50 mg) and 10% palladium on carbon (15 mg) in methanol (5 mL) is shakenunder hydrogen atmosphere (3.5 bar) at room temperature. The catalyst isfiltered off and the filtrate is concentrated in vacuo. The residue istriturated with diethyl ether, filtered off, and dried to give the titlecompound. LC (method 3): t_(R)=0.58 min; Mass spectrum (ESI⁺): m/z=440[M+H]⁺.

Example 65-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-{1-[(1-trifluoromethyl-cyclopropyl)methyl]-piperidin-4-yl}-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridineand methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl esterfollowing a procedure analogous to that described for Example 2. LC(method 3): t_(R)=0.67 min; Mass spectrum (ESI⁺): m/z=486 [M+H]⁺.

Example 75-(2-Fluoro-4-methanesulfonylmethyl-phenyl)-2-{1-[(1-trifluoromethyl-cyclopropyl)methyl]-piperidin-4-yl}-2,3-dihydrofuro[2,3-c]pyridine

The title compound is prepared from5-(2-fluoro-4-methanesulfonylmethyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridineand methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl esterfollowing a procedure analogous to that described for Example 2. LC(method 1): t_(R)=1.01 min; Mass spectrum (ESI⁺): m/z=513 [M+H]⁺.

Example 85-(4-Methanesulfonylmethyl-phenyl)-2-{1-[(1-trifluoromethyl-cyclopropyl)methyl]-piperidin-4-yl}-2,3-dihydrofuro[2,3-c]pyridine

The title compound is prepared from5-(4-methanesulfonylmethyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridineand methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl esterfollowing a procedure analogous to that described for Example 2. LC(method 1): t_(R)=0.95 min; Mass spectrum (ESI⁺): m/z=495 [M+H]⁺.

Example 95-(2-Fluoro-4-methanesulfonylmethyl-phenyl)-2-[1-(2-fluoro-2-methyl-propyl)-piperidin-4-yl]-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from1-{4-[5-(2-fluoro-4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidin-1-yl}-2-methyl-propan-2-olfollowing a procedure analogous to that described in Example 1. LC(method 1): t_(R)=0.96 min; Mass spectrum (ESI⁺): m/z=465 [M+H]⁺.

Example 10(R)-2-[1-(2-Fluoro-2-methyl-propyl)-piperidin-4-yl]-5-(4-methanesulfonyl-phenyl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from(S)-1-{4-[5-(4-methanesulfonyl-phenyl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidin-1-yl}-2-methyl-propan-2-olfollowing a procedure analogous to that described in Example 1. LC(method 4): t_(R)=0.73 min; Mass spectrum (ESI⁺): m/z=447 [M+H]⁺.

Example 11(S)-2-[1-(2-Fluoro-2-methyl-propyl)-piperidin-4-yl]-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from(S)-1-{4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidin-1-yl}-2-methyl-propan-2-olfollowing a procedure analogous to that described in Example 1. LC(method 3): t_(R)=0.62 min; Mass spectrum (ESI⁺): m/z=438 [M+H]⁺.

Example 12(R)-2-[1-(2-Fluoro-2-methyl-propyl)-piperidin-4-yl]-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from(R)-1-{4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidin-1-yl}-2-methyl-propan-2-olfollowing a procedure analogous to that described in Example 1. LC(method 3): t_(R)=0.62 min; Mass spectrum (ESI⁺): m/z=438 [M+H]⁺.

Example 13(R)-5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-{1-[(1-trifluoromethyl-cyclopropyl)methyl]-piperidin-4-yl}-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from(S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridineand methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl esterfollowing a procedure analogous to that described for Example 2. LC(method 4): t_(R)=0.64 min; Mass spectrum (ESI⁺): m/z=500 [M+H]⁺.

Example 14 and 15(R)-5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-{1-[(1-trifluoromethyl-cyclopropyl)methyl]-piperidin-4-yl}-2,3-dihydro-furo[2,3-c]pyridineand(S)-5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-{1-[(1-trifluoromethyl-cyclopropyl)methyl]-piperidin-4-yl}-2,3-dihydro-furo[2,3-c]pyridine

The title compounds are obtained in separate fractions upon SFC onchiral phase of racemic Example 6 (column: Daicel OJH, 250×20 mm; mobilephase: methanol containing 0.2% diethylamine/sc carbon dioxide 20:80;flow rate 10 ml/min). The retention times on the SFC on chiral phase(Daicel OJH, 250×4.6 mm; mobile phase: methanol containing 0.2%diethylamine/sc carbon dioxide 25:75; flow rate 4 ml/min): Example 14:t_(R)=2.70 min; Example 15: t_(R)=3.47 min.

Example 16(R)-2-[1-(2-Fluoro-2-methyl-propyl)-piperidin-4-yl]-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from(S)-1-{4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidin-1-yl}-2-methyl-propan-2-olfollowing a procedure analogous to that described for Example 1. LC(method 4): t_(R)=0.58 min; Mass spectrum (ESI⁺): m/z=452 [M+H]⁺.

Example 17(R)-5-(4-Methanesulfonyl-phenyl)-2-{1-[(1-trifluoromethyl-cyclopropyl)methyl]-piperidin-4-yl}-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from(R)-5-(4-methanesulfonyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridineand methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl esterfollowing a procedure analogous to that described for Example 2. LC(method 1): t_(R)=1.09 min; Mass spectrum (ESI⁺): m/z=481 [M+H]⁺.

Example 18(R)-5-(4-Methanesulfonyl-phenyl)-2-methyl-2-[(1-[(1-trifluoromethyl-cyclopropyl)methyl]-piperidin-4-yl]-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from(S)-5-(4-methanesulfonyl-phenyl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridineand methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl esterfollowing a procedure analogous to that described for Example 2. LC(method 4): t_(R)=0.79 min; Mass spectrum (ESI⁺): m/z=495 [M+H]⁺.

Example 19(R)-2-[1-(2-Fluoro-2-methyl-propyl)-piperidin-4-yl]-5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridine

The title compound is prepared from(S)-1-{4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidin-1-yl}-2-methyl-propan-2-olfollowing a procedure analogous to that described in Example 1. LC(method 1): t_(R)=1.02 min; Mass spectrum (ESI⁺): m/z=433 [M+H]⁺.

1. A compound of formula I

wherein: R¹ is selected from the group R¹-G1 consisting ofC₃₋₆-cycloalkyl-CH₂— and linear or branched C₁₋₅-alkyl, wherein theC₃₋₆-cycloalkyl and the C₁₋₅-alkyl groups are optionally substitutedwith one or more F atoms and/or one CF₃ group, and wherein the alkylgroup is optionally substituted from position 2 onwards; A is selectedfrom the group A-G1 consisting of a 1,2,3,6-tetrahydropyridin-4-yl ringsubstituted at the N with C₁₋₄-alkyl-S(═O)₂—, a piperidin-4-yl ringsubstituted at the N with C₁₋₄-alkyl-S(═O)₂—, and a phenyl ringsubstituted with a group T and optionally additionally substituted withone or two groups independently selected from F and CH₃; T is selectedfrom the group T-G1 consisting of F, Cl, Br, I, CN, OH, NO₂,C₁₋₆-alkyl-, C₁₋₆-alkenyl-, C₁₋₆-alkynyl-, C₃₋₆-cycloalkyl,C₁₋₆-alkyl-O—, C₃₋₆-cycloalkyl-O—, C₁₋₆-alkyl-S—, HO—C(═O)—,C₁₋₆-alkyl-O—C(═O)—, C₁₋₄-alkyl-C(═O)—, C₃₋₆-cycloalkyl-C(═O)—,C₁₋₄-alkyl-S(═O)—, C₁₋₄-alkyl-S(═O)₂—, R^(NT1)R^(NT2)N—,R^(NT1)R^(NT2)N—C(═O)—, R^(NT1)R^(NT2)N—S(═O)₂—,R^(NT1)R^(NT2)N—C(═O)—(R^(N))N—, heterocyclyl, heterocyclyl-O—, aryl,aryl-O—, heteroaryl, and heteroaryl-O—, wherein each alkyl, alkenyl,alkynyl, and cycloalkyl group is optionally substituted with one or moresubstituents independently selected from F, Cl, CN, OH, C₁₋₃-alkyl,C₃₋₆-cycloalkyl, C₁₋₃-alkyl-O—, R^(NT1)R^(NT2)N—,R^(NT1)R^(NT2)N—C(═O)—, C₁₋₄-alkyl-S(═O)—, C₁₋₄-alkyl-S(═O)₂—,R^(NT1)R^(NT2)N—S(═O)₂—, aryl, heteroaryl, and heterocyclyl, whereinaryl is phenyl or naphthyl, heteroaryl is a 5- or 6-membered aromaticring which contains 1, 2, 3, or 4 heteroatoms independently selectedfrom N, O, and S, wherein the H-atom in one or more NH groups isoptionally replaced by R^(N), heterocyclyl is a 4- to 7-memberedunsaturated or saturated carbocyclic ring in which 1 or 2 —CH₂-groupsare independently replaced by NR^(N), O, —O(═O)—, S, —S(═O)—, or—S(═O)₂—, and/or in which a —CH-group is replaced by N, and each aryl,heteroaryl, or heterocyclyl group is optionally substituted with one ormore substituents independently selected from L^(A); R^(N) isindependently selected from the group R^(N)-G1 consisting of H,C₁₋₄-alkyl, C₁₋₄-alkyl-C(═O)—, and C₁₋₄-alkyl-S(═O)₂—; R^(NT1) isselected from the group R^(NT1)-G1 consisting of H, C₁₋₆-alkyl,C₃₋₆-cycloalkyl, C₁₋₆-alkyl-C(═O)—, C₁₋₆-alkyl-S(═O)₂, heterocyclyl,aryl, and heteroaryl, wherein each alkyl and cylcoalkyl group isoptionally substituted with one or more substituents independentlyselected from the group consisting of F, OH, CN, C₁₋₄-alkyl,C₁₋₄-alkyl-O—, R^(N) ₂N, C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl,heterocyclyl, phenyl, and heteroaryl, heterocyclyl is optionallysubstituted with one or more substituents independently of each otherselected from F, C₁₋₄-alkyl, R^(N) ₂N, OH, and C₁₋₄-alkyl-O—,heterocyclyl is a C₄₋₇-cycloalkyl ring in which 1 or 2 —CH₂-groups areindependently replaced by NR^(N), O, C(═O), S, S(═O), or S(═O)₂, aryl isphenyl or naphthyl, heteroaryl is a 5- or 6-membered aromatic ring whichcontains 1, 2, or 3 heteroatoms independently selected from N, O, and S,wherein the H-atom in one or more NH groups is optionally replaced byR^(N), and aryl and heteroaryl are optionally substituted with one ormore substituents L^(A); R^(NT2) is selected from the group R^(NT2)-G1consisting of H and C₁₋₆-alkyl; or R^(NT1) and R^(NT2) are linked toform one group selected from the group R^(NT1)R^(NT2)-G1 consisting of aC₃₋₅-alkylene group, wherein 1 or 2 —CH₂-groups are independentlyreplaced by NR^(N), O, C(═O), S, S(═O), or S(═O)₂, and which areoptionally substituted with one or more substituents independentlyselected from F, C₁₋₄-alkyl, (R^(N))₂N, OH, and C₁₋₄-alkyl-O—; L^(A) isselected from the group L^(A)-G1 consisting of F, Cl, Br, CN, OH, NO₂,C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, (R^(N))₂N—C(═O), (R^(N))₂N—, andC₁₋₄-alkyl-S(═O)₂—, wherein each alkyl group is optionally substitutedwith one or more substituents independently selected from F, Cl, CN, OH,and C₁₋₃-alkyl-O—; L^(P) is selected from the group L^(P)-G1 consistingof F and C₁₋₃-alkyl, wherein the alkyl group is optionally substitutedwith one or more F-atoms; L^(Q) is selected from the group L^(Q)-G1consisting of H and C₁₋₃-alkyl; X is selected from the group X-G1consisting of CH and N; and n is an integer selected from 0, 1, 2, 3,and 4, or a tautomer, stereoisomer, or salt thereof.
 2. The compoundaccording to claim 1, wherein R¹ is 2-fluoro-2-methylpropyl or(1-trifluoromethylcyclopropyl)methyl.
 3. The compound according to claim1, wherein: A is

wherein the phenyl group is optionally additionally substituted with oneor two groups independently selected from F and CH₃.
 4. The compoundaccording to claim 1, wherein: A is

wherein the phenyl groups are optionally substituted with one or twogroups independently selected from F and CH₃.
 5. The compound accordingto claim 1 wherein: A is


6. The compound according to claim 1, wherein: X is N; R¹ is

and A is

wherein the phenyl group is optionally additionally substituted with oneor two groups independently selected from F and CH₃; T isC₁₋₄-alkyl-S(═O)₂—CH₂— or C₁₋₄-alkyl-S(═O)₂—; L^(Q) is H or CH₃; and ora pharmaceutically acceptable salt thereof.
 7. The compound according toclaim 6, wherein: A is

and L^(Q) is H or CH₃, or a pharmaceutically acceptable salt thereof. 8.A pharmaceutical composition comprising a compound according to claim 1and an inert carrier or diluent.
 9. A method for treating diseases orconditions which are mediated by activating the G-protein-coupledreceptor GPR119 in a patient in need thereof, the method comprisingadministering to the patient a pharmaceutically effective amount of acompound according to claim
 1. 10. The method according to claim 1,wherein the disease or condition which are mediated by activating theG-protein-coupled receptor GPR119 is diabetes, obesity, or dyslipidemia.